Clinical trial NCT02024607
Conditions: Advanced Gastrointestinal Cancer
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2014-01-01; Completion date: 2019-11-01
Enrollment: 495 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, multi-center, Phase 1/2 dose escalation study of BBI608 administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan.

Detailed description:
This is an open label, multi-center, Phase 1/2 dose escalation study of BBI608 administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan. A study cycle will consist of daily and continuous oral administration of BBI608 for four weeks (28 days) in combination with FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan.

Arms: arm 1: BBI608 is administered orally twice daily, continuously. Oxaliplatin 85 mg/m\^2 together with leucovorin 400 mg/m\^2 will be administered intravenously. 5-FU 400 mg/m\^2 bolus will be administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m\^2/day (total 2400 mg/m\^2 over 46-48 hours) continuous intravenous infusion. This regimen will be repeated every 14 days thereafter. arm 2: BBI608 is administered orally twice daily, continuously. Oxaliplatin 85 mg/m\^2 together with leucovorin 400 mg/m\^2 will be administered intravenously. 5-FU 400 mg/m\^2 bolus will be administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m\^2/day (total 2400 mg/m\^2 over 46-48 hours) continuous intravenous infusion. Bevacizumab 5 mg/kg will be administered intravenously following oxaliplatin/leucovorin infusion. This regimen will be repeated every 14 days thereafter. arm 3: BBI608 is administered orally twice daily, continuously. CAPOX regimen will be administered orally (capecitabine) and IV (oxaliplatin). Capecitabine 850 mg/m\^2 will be administered orally twice-daily for 14 consecutive days and be repeated every 21 days. Oxaliplatin will be administered IV and be repeated every 21 days thereafter. If capecitabine is tolerated at the 850 mg/m\^2 twice daily dose, dosage may be increased to 1000 mg/m\^2 twice daily as tolerated after the first cycle. arm 4: BBI608 is administered orally twice daily, continuously. Irinotecan 180 mg/m\^2 together with leucovorin 400 mg/m\^2 will be administered intravenously. 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 every 14 days thereafter. arm 5: BBI608 is administered orally twice daily, continuously. Irinotecan 180 mg/m\^2 together with leucovorin 400 mg/m\^2 will be administered intravenously 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. Bevacizumab 5 mg/kg will be administered intravenously following oxaliplatin/leucovorin infusion. This regimen will be repeated every 14 days thereafter. arm 6: BBI608 is administered orally twice daily, continuously. Regorafenib 120 mg will be administered orally once daily, with a low-fat meal and be continued for 21 consecutive days of every 28 days thereafter. If regorafenib is tolerated in the first cycle, dosage may be increased to 160 mg once daily as tolerated after the first cycle. arm 7: BBI608 is administered orally twice daily, continuously. Irinotecan 180 mg/m\^2 will be administered intravenously. This regimen will be repeated every 14 days thereafter.
Interventions: intervention 1: BBI608 intervention 2: Fluorouracil intervention 3: Oxaliplatin intervention 4: Leucovorin intervention 5: Irinotecan intervention 6: Bevacizumab intervention 7: Capecitabine intervention 8: Regorafenib
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None

Protocol documents:
Prot_000.pdf: 
Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 1 
 
 
TITLE: 
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Standard Chemotherapies in Adult Patients with 
Advanced Gastrointestinal Cancer 
PROTOCOL NUMBER: 
BBI608-246 
STUDY DRUG: 
BBI608 
SPONSOR: 
Boston Biomedical, Inc. 
640 Memorial Drive 
Cambridge, MA 02139 
Telephone: (617) 674-6800 
Fax:  (617) 674-8662 
 
MEDICAL MONITOR: 
Laura Borodyansky, MD 
SAFETY FAX: 
(617) 674-8662 
SAFETY CONTACT: 
(617) 674-6800 x 8705 
DATE OF PROTOCOL: 
September 17th, 2013 
AMENDMENT 1: 
September 26th, 2015 
AMENDMENT 2: 
August 17th, 2016 
AMENDMENT 3: 
December 6th, 2016 
AMENDMENT 4: 
June 23rd, 2017 
 
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. 


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SYNOPSIS 
Study Title: 
A Phase Ib/II Clinical Study of BBI608 in Combination with 
Standard Chemotherapies in Adult Patients with Advanced 
Gastrointestinal Cancer  
Study Number: 
BBI608-246 
Study Phase:  
Phase Ib/II 
Study Drug: 
BBI608, a novel investigational small molecule anticancer drug that targets 
cancer stem cells.  
Primary Objectives:  
Phase Ib: 
To determine the safety, tolerability and preliminary anti-tumor activity of 
BBI608 when administered in combination with FOLFOX6 with and without 
bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, 
regorafenib or irinotecan in adult patients with advanced gastrointestinal (GI) 
cancer. 
Phase II: 
To assess the objective response rate (ORR) of BBI608 administered in 
combination with FOLFIRI (with bevacizumab if clinically indicated) in 
patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer 
(mCRC). 
Secondary 
Objectives: 
To determine the pharmacokinetic profile of BBI608 administered in 
combination with FOLFOX6 with and without bevacizumab or CAPOX or 
FOLFIRI with and without bevacizumab or regorafenib. 
To determine the pharmacodynamics (biomarkers) of BBI608 administered in 
combination with FOLFOX6 with and without bevacizumab or CAPOX or 
FOLFIRI with and without bevacizumab, regorafenib or irinotecan. 
To assess the preliminary anti-tumor activity of BBI608 administered in 
combination with FOLFOX6 with and without bevacizumab or CAPOX or 
FOLFIRI with and without bevacizumab, regorafenib or irinotecan.  
To assess the disease control rate (DCR), progression free survival (PFS), and 
overall survival (OS) of BBI608 administered in combination with FOLFIRI 
(with bevacizumab if clinically indicated) in patients with FOLFIRI/XELIRI-
refractory mCRC. 
Study Design: 
 
This is an open label, multi-center, Phase Ib study of BBI608 administered in 
combination with either FOLFOX6 with and without bevacizumab, or 
CAPOX, or FOLFIRI with and without bevacizumab, regorafenib or 
irinotecan.  A study cycle will consist of daily and continuous oral 
administration of BBI608 for four weeks (28 days) in combination with 
FOLFOX6 with and without bevacizumab, or CAPOX or FOLFIRI with and 
without bevacizumab, regorafenib or irinotecan.  Cycles will be repeated until 
disease progression, unacceptable toxicity, or another discontinuation criterion 
is met.  
Arm A (FOLFOX6) – Starting on day (-) 5 of cycle 1, BBI608 will be 
administered continuously twice daily with doses separated by approximately 
12 hours. On Cycle 1 Day 1 (C1D1), a standard FOLFOX6 regimen will begin 
and will be repeated every 14 days thereafter. In the case of toxicity, dose 
adjustment is permitted.  


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Arm B (FOLFOX6 with bevacizumab) – Starting on day (-) 5 of cycle 1, 
BBI608 will be administered continuously twice daily with the doses separated 
by approximately 12 hours in 28 day cycles. On Cycle 1 Day 1 (C1D1), a 
standard FOLFOX6 with bevacizumab regimen will begin and be repeated 
every 14 days thereafter. In case of toxicity, dose adjustment is permitted. 
Arm C (CAPOX) – Starting on day (-) 5 of cycle 1, BBI608 will be 
administered continuously twice daily with doses separated by approximately 
12 hours in 28 day cycles. On Cycle 1 Day 1 (C1D1), a standard CAPOX 
regimen will begin and will be repeated every 21 days thereafter. In the case of 
toxicity, dose adjustment is permitted.  
Arm D (FOLFIRI) – Starting on day (-) 5 of cycle 1, BBI608 will be 
administered continuously twice daily with doses separated by approximately 
12 hours in 28 day cycles. On Cycle 1 Day 1 (C1D1), a standard FOLFIRI 
regimen will begin and be repeated every 14 days thereafter.  In case of 
toxicity, dose adjustment is permitted.   
Arm E (FOLFIRI with bevacizumab) – Starting on day (-) 5 of cycle 1, BBI608 
will be administered continuously twice daily with the doses separated by 
approximately 12 hours in 28 day cycles. On Cycle 1 Day 1 (C1D1), a standard 
FOLFIRI with bevacizumab regimen will begin and be repeated every 14 days 
thereafter.  In case of toxicity, dose adjustment is permitted. 
Arm F (regorafenib) – Starting on day (-) 5 of cycle 1, BBI608 will be 
administered continuously twice daily with doses separated by approximately 
12 hours. On Cycle 1 Day 1 (C1D1), patients will receive regorafenib 120 mg 
once daily, with a low-fat meal, for 21 consecutive days of every 28 days 
thereafter. In case of toxicity, dose adjustment is permitted. If regorafenib is 
tolerated in the first cycle, dosage may be increased to 160 mg once daily as 
tolerated after first cycle.          
Arm G (irinotecan) - Starting on day (-) 5 of cycle 1, BBI608 will be 
administered continuously twice daily with the doses separated by 
approximately 12 hours in 28 day cycles. On Cycle 1 Day 1 (C1D1), irinotecan 
180 mg/m2 will begin and be repeated every 14 days thereafter.  In case of 
toxicity, dose adjustment is permitted.                                                                     
Initially, 3 patients will be enrolled in each combination arm (except for the 
irinotecan study arm for which enrollment will begin with the expansion phase 
skipping DLT period assessment being that RP2D for BBI608 in combination 
with irinotecan has been established at the time of this amendment*) at a 
BBI608 dose level of 240 mg twice daily (480 mg total daily dose—Cohort I).  
If 0 out of 3 patients experience a DLT, then the BBI608 dose will be escalated 
to 480 mg twice daily (960 mg total daily dose—Cohort II) and 6 patients will 
be enrolled at this dose level. If 1 out of 3 patients in the 240 mg by mouth 
twice daily cohort experience a DLT, then an additional 3 patients will be 
enrolled in that arm.  If a DLT occurs in ≥ 2 of the 6 patients in an arm, then 
the BBI608 dose will be reduced to 160 mg twice daily (320 mg total daily 
dose—Cohort Ib) and 6 patients will be enrolled at this does level.  
If ≤1 of 6 patients experience a DLT at the 240 mg by mouth twice daily dose 
level, then BBI608 dose will be escalated to 480 mg by mouth twice daily (960 
mg total daily dose) and 6 patients will be enrolled at this dose level. If ≤ 1 out 
of 6 patients experiences a DLT at 480 mg by mouth twice daily, this dose 
level will be considered the Recommended Phase 2 Dose (RP2D) for BBI608 
in that combination.  
If ≥2 out of 6 patients experience a DLT at 480 mg by mouth twice daily, then 
RP2D will be declared as the next lowest dose level at which ≤1 out of 6 


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patients experiences a DLT. 
Safety of BBI608 at 480 mg by mouth twice daily (960 mg total daily dose) 
may be evaluated in each combination arm, including if a lower RP2D has 
previously been established in that combination based on acceptable safety and 
efficacy profile, for as long as <1 of 6 patients experience a DLT at the 240 mg 
by mouth twice daily dose level (480 mg total daily dose). DLT assessment 
will be performed as above with 6 patients enrolled at the dose of 480 mg by 
mouth twice daily (960 mg total daily dose). Up to an additional 15 evaluable 
patients may be enrolled in each cohort at the dose of 480 mg by mouth twice 
daily (960 mg total daily dose) as long as <1 of 6 patients experience a DLT at 
the 480 mg by mouth twice daily dose level (960 mg total daily dose). 
A trial arm of BBI608 in combination with FOLFOX6 with and without 
bevacizumab or CAPOX or FOLFIRI with and without bevacizumab, 
regorafenib or irinotecan will continue to enroll patients only if no more than 1 
out of 6 patients for each combination experience a protocol-defined DLT. It is 
expected that, for each combination arm, approximately 9 to 12 patients will be 
enrolled in the dose escalation part of the study and up to an additional 15 
evaluable patients may be enrolled at RP2D. An additional 20 evaluable 
subjects will be enrolled on the hepatocellular carcinoma, cholangiocarcinoma, 
gastric/GEJ, esophageal or pancreatic adenocarcinoma disease cohorts.  
Up to an additional 50 evaluable FOLFIRI/XELIRI-refractory colorectal 
(CRC) patients will be enrolled on the FOLFIRI study arm (with bevacizumab 
if clinically indicated) as an expansion cohort. FOLFIRI/XELIRI-refractory 
CRC patients will have failed treatment with FOLFIRI/XELIRI with or without 
bevacizumab regimen with failure defined as progression of disease during or 
<3 months after the last dose of FOLFIRI/XELIRI with or without 
bevacizumab.  For the XELIRI/FOLFIRI-refractory CRC patients enrolled on 
the expansion cohort for whom bevacizumab is clinically indicated, 
bevacizumab 5 mg/kg will be administered intravenously following 
irinotecan/leucovorin infusion. In case of toxicity, dose adjustment is 
permitted. 
A study cycle will consist of 28 days of daily administration of BBI608 in 
combination with FOLFOX6 with and without bevacizumab or CAPOX or 
FOLFIRI with and without bevacizumab, regorafenib or irinotecan. 
Pharmacokinetic (PK) and pharmacodynamic assessments will be performed in 
the first cycle only for each drug combination. If there is an indication of drug 
accumulation, PK assessment can be performed for more than two cycles. 
Safety and tolerability of BBI608 in combination with FOLFOX6 with and 
without bevacizumab or CAPOX or FOLFIRI with and without bevacizumab, 
regorafenib or irinotecan will be assessed for the duration of study treatment 
and for 30 days after the last dose of BBI608. Evaluation of anti-tumor activity 
of BBI608 in combination with FOLFOX6 with and without bevacizumab or 
CAPOX or FOLFIRI with and without bevacizumab, regorafenib or irinotecan 
will be performed at 8 week intervals while patients remain on study according 
to RECIST 1.1. Patients will have confirmatory radiographic scanning within 
approximately 4 weeks of initial results of partial or complete response (PR or 
CR) according to RECIST 1.1.  
Study Population:  
 
This study will enroll patients with advanced gastrointestinal cancer for which 
a protocol chemotherapy regimen is an appropriate treatment option in the 
judgment of the Physician Investigator.  Examples of gastrointestinal cancers 
potentially eligible for protocol therapy include colorectal cancer (CRC), 
hepatocellular 
carcinoma 
(HCC), 
pancreatic 
adenocarcinoma, 
cholangiocarcinoma, and gastro-esophageal carcinoma.  Patients may be 


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treatment-naïve or may have received standard chemotherapy; including  
regimens containing fluoropyrimidine, or oxaliplatin, or irinotecan, or 
regorafenib, or bevacizumab.  Additional key inclusion criteria include:  
Karnofsky performance status score of > 70%, a life expectancy of greater than 
3 months, and adequate bone marrow, renal and hepatic function.  Patient 
accrual will occur over a period of time dependent upon the enrollment rate of 
the study.  
Test Product, Dose, 
and Mode of 
Administration:  
 
Patients in this trial will receive BBI608 orally twice daily, approximately one 
hour prior to or two hours after meals with the first dose given in the morning 
and doses separated by approximately 12 hours.  
For patients receiving FOLFOX6, a standard FOLFOX6 regimen will begin 
administration on day 1 cycle 1 and will subsequently be repeated every 14 
days thereafter, or twice per 28 day cycle. 
For patients receiving FOLFOX6 with bevacizumab, a standard FOLFOX6 
with bevacizumab regimen will begin administration on day 1 cycle 1 and will 
subsequently be repeated every 14 days thereafter, or twice per 28 day cycle. 
For patients receiving CAPOX, a standard CAPOX regimen will begin 
administration on day 1 of cycle 1 and will subsequently be repeated every 21 
days thereafter. 
For patients receiving FOLFIRI, a standard FOLFIRI regimen will begin 
administration on day 1 of cycle 1 and will subsequently be repeated every 14 
days thereafter, or twice per 28 day cycle. FOLFIRI-refractory patients 
enrolled as part of the expansion cohort can resume FOLFIRI at the last dose 
that they received prior to progression on FOLFIRI. 
For patients receiving FOLFIRI with bevacizumab, a standard FOLFIRI with 
bevacizumab regimen will begin administration on day 1 cycle 1 and will 
subsequently be repeated every 14 days thereafter, or twice per 28 day cycle.  
For patients receiving regorafenib, 120 mg will be taken orally once daily 
starting on day 1 of cycle 1 for 21 consecutive days of every 28 days thereafter. 
If regorafenib is tolerated in the first cycle, dosage will be increased to 160 mg 
once daily as tolerated after the first cycle. 
For patients receiving irinotecan, irinotecan 180 mg/m2 will begin 
administration on day 1 of cycle 1 and will subsequently be repeated every 14 
days thereafter, or twice per 28 day cycle.  
Cycles will be repeated until progression of disease, unacceptable toxicity, or 
another discontinuation criterion is met.   
Duration of 
Treatment:  
For an individual patient, treatment with BBI608 and the combination drug will 
continue until unacceptable toxicity, disease progression (clinical or 
radiological) or another discontinuation criterion is met.  It is expected that 
most patients will receive between one and four cycles of BBI608 for a 
treatment period of 4 to 16 weeks.  


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Criteria for 
Determination of 
Dose-Limiting 
Toxicity: 
 
A DLT is defined by the occurrence of any of the following toxicities possibly 
or probably related to BBI608, or BBI608 in combination with FOLFOX6 with 
and without bevacizumab, or CAPOX, or FOLFIRI with and without 
bevacizumab, regorafenib or irinotecan within the 28 days of Cycle 1: 
● CTCAE (Common Terminology Criteria for Adverse Events) Grade 4 
hematological toxicity. 
● 
Grade 
3 
or 
4 
non-hematological 
toxicity, 
except 
Grade 
3 
nausea/vomiting/anorexia, diarrhea, or fatigue will be considered a DLT only if 
it persists more than three (3) days despite optimal medical management; and 
alopecia will not be considered a DLT. 
● Any other toxicity that in the view of the Principal Investigator represents a 
clinically significant hazard to the patient. 
Whether a DLT has occurred will be assessed during the first 28 days of 
BBI608 therapy.  Subjects who received fewer than 28 consecutive days of 
BBI608 dosing due to toxicity will be eligible for DLT assessment. DLT will 
be determined from adverse events, changes from baseline in physical 
examination findings and laboratory parameters.  The incidence of adverse 
events and DLTs will be evaluated for each combination arm and for all 
patients.   
Pharmacokinetic 
and 
Pharmacodynamic 
Variables: 
Pharmacokinetic variables to be determined include maximum plasma drug 
concentration (Cmax), volume of distribution, area under the time-
concentration curve (AUC), distribution half-life, and terminal half-life.  PK 
draws in FOLFOX6 with and without bevacizumab, and FOLFIRI with and 
without bevacizumab, and regorafenib arms will be performed beginning on 
day 1 and day 15 of Cycle 1. PK draws in the CAPOX arm will be performed 
beginning on day 1 and day 22 of Cycle 1.  PK draws will not be collected for 
the irinotecan arm. Response (increase or decrease) of several biomarkers as 
well as intratumoral concentration of BBI608 from biopsied tumors following 
BBI608 administration will be examined in patients with accessible tumors 
who consent to an optional biopsy. Tumor biopsies will be collected prior to 
the first dose of BBI608 and on day 1 of cycle 2 for patients with accessible 
tumors. 
Statistical Methods:  
 
Phase Ib: 
All patients receiving at least one daily dose of BBI608 will be considered 
evaluable for safety analyses.  In addition to the evaluation and categorization 
of adverse events, listings of laboratory test results collected at baseline and 
during the study will be generated.  Descriptive statistics summarizing the 
changes in those laboratory tests over time will be presented.  Patients who 
have received at least one cycle of BBI608 and who have had at least one 
disease assessment following the initiation of therapy will be considered 
evaluable for response.  The anti-tumor activity will be evaluated on an 
exploratory basis and will be summarized using descriptive statistics or 
graphics. 
 
Phase II: 
The primary endpoint, ORR, will be determined for FOLFIRI-refractory CRC 
patients as a single stage design. This analysis will test the following: 
Ho: π ≤ 0.05 
Versus 
Ha: π > 0.05 
If ORR response rate with FOLFIRI treatment alone is estimated at 5% and a 


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true ORR response rate with FOLFIRI (with bevacizumab if clinically 
indicated) in combination with BBI608 is 12%, a sample size of 50 evaluable 
patients produces a two-sided 95% confidence interval with a width of 0.2, for 
a 95% exact confidence interval of 4.5%-24.5%. 
 
 


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DOSE ESCALATION SCHEME 
BBI608-246: A Phase 1b Clinical Trial  
 
Cohort 
No. 
Subjects# 
Dose 
Level 
Total Daily 
Dose of  
BBI608 
I  
3 
Level 1 
480 mg 
Ib* 
3 
Level 1b 
320 mg 
II** 
3 
Level 2 
960 mg 
         # Groups may be expanded to six subjects, as provided in the protocol. 
          *This cohort will be created if DLT is observed in ≥2 of 6 patients at dose level 1 (480 mg) 
** This cohort may be created if a lower RP2D has been previously established based on acceptable safety and 
efficacy profile, for as long as <1 of 6 patients experience a DLT at the 240 mg by mouth twice daily dose 
level (480 mg total daily dose). 
 
  


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Table of Contents 
SYNOPSIS .................................................................................................................................2 
DOSE ESCALATION SCHEME ..............................................................................................8 
1 
PRECLINICAL SUMMARY AND STUDY RATIONALE ..........................................15 
1.1 
Scientific Background of BBI608 ..........................................................................15 
1.2 
Preclinical Efficacy ................................................................................................15 
1.3 
GLP Toxicology.....................................................................................................16 
1.4 
Safety and Encouraging Signs of Antitumor Activity in Phase I and II Studies ...17 
1.5 
Safety and Encouraging Signs of Antitumor Activity in the BBI608-246 Study ..17 
2 
STUDY OBJECTIVES ....................................................................................................19 
2.1 
Primary Objectives.................................................................................................19 
2.2 
Secondary Objectives.............................................................................................19 
3 
SELECTION OF STUDY POPULATION .....................................................................20 
3.1 
Inclusion Criteria ...................................................................................................20 
3.2 
Exclusion Criteria ..................................................................................................21 
3.3 
Number of Patients ................................................................................................24 
4 
INVESTIGATIONAL PLAN ..........................................................................................25 
4.1 
Overall Study Design .............................................................................................25 
4.2 
Rationale for Study Design ....................................................................................27 
4.3 
Selection of Dose ...................................................................................................27 
4.4 
Criteria for Dose Escalation and Determination of Dose-Limiting Toxicity ........28 
4.5 
Dose-Limiting Toxicity .........................................................................................28 
4.6 
Study Duration .......................................................................................................29 
5 
STUDY VISITS ...............................................................................................................29 
5.1 
Overview ................................................................................................................29 
5.2 
Informed Consent...................................................................................................29 
5.3 
Pre-Study Evaluations (Baseline) ..........................................................................29 
5.4 
On-Study Assessments...........................................................................................30 
5.5 
Tumor Evaluation Visits ........................................................................................41 
5.6 
End of Study Evaluation ........................................................................................41 
5.7 
Discontinuation from Study ...................................................................................42 
6 
STUDY PROCEDURES .................................................................................................42 
6.1 
Medical History .....................................................................................................42 
6.2 
Physical Examination.............................................................................................42 
6.3 
Clinical Laboratory Tests .......................................................................................43 
6.4 
Pharmacokinetic Assessments ...............................................................................43 
6.5 
Pharmacodynamic Assessments ............................................................................43 
6.6 
Tumor Biopsy ........................................................................................................43 
7 
TREATMENT .................................................................................................................44 
7.1 
BBI608 ...................................................................................................................44 
7.2 
Dose Modifications ................................................................................................46 
7.3 
Treatment Compliance ...........................................................................................46 
7.4 
Blinding..................................................................................................................47 
7.5 
Prior Treatment ......................................................................................................47 
7.6 
Concomitant Medication ........................................................................................47 
8 
SAFETY ASSESSMENTS ..............................................................................................48 


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8.1 
Adverse Events ......................................................................................................48 
8.2 
Serious Adverse Events .........................................................................................49 
9 
ASSESSMENT OF ANTI-TUMOR ACTIVITY ............................................................50 
9.1 
Central Radiology Review .....................................................................................50 
9.2 
Methods of Measurement ......................................................................................51 
9.3 
Baseline Documentation of “Target” and “Non-Target” Lesions .........................51 
9.4 
Response Criteria ...................................................................................................52 
9.5 
Evaluation of Best Overall Response ....................................................................52 
10 PLANNED STATISTICAL METHODS ........................................................................52 
10.1 
General Considerations ..........................................................................................52 
10.2 
Determination of Sample Size ...............................................................................53 
10.3 
Analysis Populations ..............................................................................................53 
10.4 
Demographics and Baseline Characteristics ..........................................................53 
10.5 
Statistical Analysis of Pharmacokinetic Variables ................................................54 
10.6 
Safety Analysis ......................................................................................................54 
11 QUALITY CONTROL AND ASSURANCE .................................................................54 
11.1 
Compliance with the Protocol ................................................................................54 
11.2 
Registration and Enrollment ..................................................................................55 
11.3 
Removal, Replacement, or Early Withdrawals of Subjects ...................................55 
12 COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL  CONSIDERATIONS 
AND INFORMED CONSENT ........................................................................................55 
12.1 
Institutional Review Board ....................................................................................55 
12.2 
Compliance with Good Clinical Practice and Ethical Considerations ...................56 
12.3 
Informed Consent and Permission to Use Private Health Information ..................56 
13 STUDY MANAGEMENT ..............................................................................................57 
13.1 
Amendments to the Protocol ..................................................................................57 
13.2 
Investigator Brochure and Information Materials ..................................................57 
13.3 
Pre-investigational Documents ..............................................................................57 
13.4 
Drug Inventory Record ..........................................................................................57 
13.5 
Disposition of Used and Unused Study Drug ........................................................58 
13.6 
Study Records ........................................................................................................58 
13.7 
Record Retention ...................................................................................................58 
13.8 
Subject Confidentiality ..........................................................................................58 
13.9 
Monitoring .............................................................................................................58 
13.10 Case Report Form (CRF) Completion ...................................................................59 
13.11 Final Site Report ....................................................................................................59 
13.12 Final Study Report .................................................................................................59 
13.13 Use of Information .................................................................................................59 
13.14 Publication .............................................................................................................60 
13.15 Research Outside the Terms of this Protocol .........................................................60 
APPENDIX A:  SCHEDULE OF ASSESSMENTS FOR FOLFOX6 WITH OR WITHOUT 
BEVACIZUMAB (ARMS A AND B) ............................................................................61 
APPENDIX B:  SCHEDULE OF ASSESSMENTS FOR CAPOX ARM (ARM C) .............62 
APPENDIX C:  SCHEDULE OF ASSESSMENTS FOR FOLFIRI WITH OR WITHOUT 
BEVACIZUMAB OR IRINOTECAN (ARMS D, E OR G) ..........................................63 
APPENDIX D:  SCHEDULE OF ASSESSMENTS FOR REGORAFENIB (ARM F) .........64 


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APPENDIX E:  PERFORMANCE STATUS .........................................................................65 
APPENDIX F:  PHARMACOKINETIC STUDIES ...............................................................66 
APPENDIX G: TUMOR BIOPSIES .......................................................................................71 
SPONSOR SIGNATURE ........................................................................................................73 
INVESTIGATOR’S SIGNATURE .........................................................................................74 
REFERENCES ........................................................................................................................75 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
ALT 
Alanine transaminase (SGPT) 
ANOVA 
Analysis of variance 
AP 
Alkaline phosphatase 
AST 
Aspartate transaminase (SGOT) 
AUC 
Area under the time-concentration curve 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CDER 
Center for Drug Evaluation and Research 
Cmax 
Maximum plasma drug concentration 
Cmin 
Minimum plasma drug concentration 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CV 
Coefficient of variation 
CTCAE 
Common terminology criteria for adverse events 
DLT 
Dose limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
Hct 
Hematocrit 


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HED 
Human equivalent dose 
Hgb 
Hemoglobin 
HGF 
Hepatocyte growth factor 
HIPAA 
Health Information Portability and Accountability Act 
IC50 
Inhibitory concentration, 50% 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
LD 
Longest diameter 
LDH 
Lactic dehydrogenase 
MR 
Minor response 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
No observable adverse effect level 
NOEL 
No observable effect level 
ORR 
Overall response rate 
PD 
Progressive disease 
PK 
Pharmacokinetic 
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended Phase 2 dose 
RBC 
Red blood cell (count) 
SAE 
Serious adverse event 
SD 
Stable disease 
SE 
Standard error  


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SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
Tmax 
Time to maximum plasma concentration 
TNM Scale 
Tumor node metastases scale 
ULN 
Upper limits of normal 
WBC 
White blood cell (count) 


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1 PRECLINICAL SUMMARY AND STUDY RATIONALE  
 
1.1 Scientific Background of BBI608 
Recent studies have uncovered the presence of cancer stem cells (CSC, also called tumor initiating cells 
or cancer stem-like cells) which have self-renewal capability and are considered to be fundamentally 
responsible for malignant growth, relapse and metastasis. Importantly, CSCs are inherently resistant to 
conventional therapies. Therefore, a targeted agent with activity against cancer stem cells holds great 
promise for cancer patients (Boman and Wicha, 2008; Clevers, 2011; Lobo et al., 2007; Magee et al., 
2012; Singh and Settleman, 2010). 
 
BBI608 is a small molecule that targets cancer by blocking self-renewal of and inducing apoptosis in 
cancer stem cells. While not a kinase inhibitor, BBI608 works by inhibiting the STAT3 pathway. With 
our proprietary target discovery technology TPIV®, scientists at Boston Biomedical, Inc. have discovered 
that the STAT3 pathway activity is critical for the self-renewal and survival of cancer stem cells in human 
cancer, including gastrointestinal malignancies such as colorectal, pancreatic, and gastric/GEJ 
adenocarcinoma. 
 
STAT3 is closely linked to another important downstream oncogene, β-catenin (Kawada et al., 2006). 
The later contributes to tumorigenesis and metastasis in colorectal cancer (CRC) as a result of APC 
mutation and is implicated in other gastrointestinal malignancies such as gastroesophageal 
adenocarcinoma, cholangiocarcinoma, hepatoma and pancreatic adenocarcinoma (White et al., 2012). 
Additionally, nuclear β-catenin localization has important clinical implications and is associated with 
CSC-promoting epithelial-to-mesenchymal transition (EMT) (Schmalhofer et al., 2009). STAT3 
activation leads to nuclear accumulation of β-catenin in CRC cells leading to increased cancer stem cell 
abundance and worse prognosis in this subset of CRC patients (Kawada et al., 2006). Similar to STAT3 
dysregulation predicting poor prognosis in CRC, increase in nuclear β-catenin predicts poor outcome in 
CRC (Morikawa et al., 2011). Furthermore, combination of nuclear β-catenin with high p-STAT3 levels 
is associated with the worst prognosis of all in CRC (Kawada et al., 2006).  Blockade of the STAT3 
pathway, therefore, offers a novel and potentially highly effective strategy to target cancer stem cells as 
well as the bulk of the heterogeneous cancer cells, while sparing normal cells and normal adult stem cells.  
 
1.2 Preclinical Efficacy 
Cancer stem cells are intrinsically resistant (more than 5 to 10 fold) to chemotherapeutic drugs. BBI608 
has potent activity (~100 to 500 nM) against cancer stem cells in vitro and in vivo while sparing normal 
hematopoietic stem cells (IC50 not reached at 30 μM), thereby offering a wide therapeutic window. The 
dependence on STAT3 is conserved in various non-stem cancer cells. BBI608 has demonstrated in vitro 
efficacy in a broad spectrum of human cancer cell lines derived from both solid tumors and hematologic 
malignancies (IC50 ~100 nM to 500 nM). BBI608 monotherapy has demonstrated potent anti-tumor 
activity in vivo in multiple murine xenograft models of human cancer, including liver, head and neck, 
breast, prostate, colon, gastric and pancreatic cancers, in the absence of adverse effects. Additionally, 
BBI608 monotherapy has demonstrated antimetastatic activity using in vivo spontaneous metastasis 
mouse models.  
 
When administered in mouse xenograft model, chemotherapeutic agents, including 5-FU, oxaliplatin, 
irinotecan, regorafenib increase pSTAT3 levels and enrich cancer stem cells abundance.  BBI608 is able 
to significantly decrease pSTAT3 levels as well as deplete stem cell abundance, and blocks the induction 


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of pSTAT3 and cancer stem cells by chemotherapeutic agents. Similar encouraging preclinical data is 
seen when BBI608 is combined with either irinotecan, or oxaliplatin, or regorafenib. In vitro, treatment 
with BBI608 combined with irinotecan or oxaliplatin or regorafenib results in potent and synergistic 
colony formation inhibition in multiple CRC cell lines. Additionally, combined treatment with BBI608 
and irinotecan or oxaliplatin or regorafenib suppresses levels of p-STAT3 and β-catenin, while 
monotherapy with irinotecan or oxaliplatin or regorafenib leads to upregulation of these proteins. Tumor 
tissue of combination-treated animals reveals synergy with increase in cancer cell death and decrease in 
tumor cell proliferation. In in vivo mouse CRC xenograft model, combination treatment of BBI608 with 
regorafenib completely suppresses tumor growth, while being safe and well tolerated by the animals.  
These data suggest broad potential of BBI608 for a wide variety of human gastrointestinal cancers. 
 
1.3 GLP Toxicology  
GLP 28-day repeat dose toxicology studies were performed in both rats and dogs at doses of 10, 30 and 
100 mg/kg/day of BBI608 by oral gavage.   
In the rat study, 100 mg/kg was not tolerated by the male rats. Toxic observations include significant 
weight loss, soft feces and diarrhea, and decreased food consumption, which led to early sacrifice. These 
observations recovered in the remaining male rats within 14 days after termination of dosing. Female rats 
receiving 100 mg/kg/day showed weight loss during the first week of dosing, however, weight gain 
recovered during the continued dosing phase without significant abnormal clinical observations.  
In the rat study, abnormal laboratory findings (azotemia, hyponatremia, hypochloremia, hyperkalemia, 
polycythemia, neutrophilia, monocytosis, and lymphopenia) were observed primarily in moribund male 
rats dosed at 100 mg/kg. These findings are consistent with acute renal failure in the setting of 
dehydration and diarrhea. In rats dosed at 100 mg/kg for 28 days, there was mild decrease in sodium, 
chloride and albumin levels and mild elevation of white blood cells, red blood cells, neutrophils, 
lymphocytes and monocytes. No significant abnormal laboratory findings were seen in recovered rats, 
suggesting these abnormal laboratory findings are reversible. There were no abnormal laboratory findings 
in rats dosed at 10 and 30 mg/kg.  
In the rat study, histopathological findings were noted in the rats dosed at 100 mg/kg, primarily in 
moribund male rats, including microscopic changes in the stomach and urinary bladder (focal or 
multifocal chronic ulceration, epithelial hyperplasia, chronic active inflammation or hemorrhagic 
changes), in lymphoid tissues (mild to marked lymphoid atrophy with mild to moderate lymphocyte 
apoptosis in thymus; mild to moderate lymphoid atrophy and mild to moderate mastocytosis in 
mesenteric lymph nodes; mild to moderate lymphoid atrophy in 2 moribund male rats of the 100 mg/kg 
group and some elevation of hemosiderosis in the spleen) and in adrenal glands (mild cortical 
vacuolation). These findings are considered non-specific changes related to the test vehicle in the setting 
of dehydration and diarrhea. There were no significant histopathological findings in recovered rats, 
suggesting these histopathological changes are reversible. There was no significant test vehicle related 
microscopic changes in rats dosed at 30 mg/kg and 10 mg/kg.  
In the rat study, toxicokinetics showed that all dose groups in rats achieved BBI608 exposure well above 
the predicted exposure levels needed for efficacy with exposure lasting beyond 10 hours.  
For the dog study, toxicity was observed in dogs receiving 100 mg/kg/day consisting of mild weight loss, 
as well as clinical observations including emesis, diarrhea, mucoid and soft feces. These adverse effects 
were reversible within 14 days in the setting of continued dosing. No treatment related clinical pathology, 
gross pathology or histopathological effects were observed at any dose level. All dose groups achieved 
plasma levels of BBI608 above the predicted levels needed for efficacy, with exposure lasting beyond 10 
hours.  


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The no observable adverse effect level (NOAEL, based on clinical observation, laboratory tests, gross and 
histopathological changes) for rats administered BBI608 daily orally over 28 days was 30 mg/kg/day 
(human equivalent dose: 180 mg/m2) and the NOAEL in dogs administered BBI608 daily orally over 28 
days was 30 mg/kg/day (human equivalent dose: 600 mg/m2). 
1.4 Safety and Encouraging Signs of Antitumor Activity in Phase I and II Studies 
In the Phase I dose escalation study of BBI608 monotherapy, 14 cohorts (N=41) were dosed from 20 mg 
to 2000 mg/day.  All of the patients in this study were in the last line of treatment. Eighteen (44%) of the 
patients had CRC, representing the most common type of cancer studied in this trial. Other types of 
cancers varied from 2-7% of the total, including gastric/GEJ, pancreatic, NSCLC, prostate, head and 
neck, melanoma and others.  Vast majority of the patients (78%) in this study progressed on >3 prior 
regimens.. Adverse events were generally mild, including grade 1-2 diarrhea, nausea, anorexia and fatigue 
with a total of 4 grade 3 events (diarrhea and fatigue). MTD was not reached. At 400 mg/day the plasma 
concentration of BBI608 was sustained at a concentration > 1.5 uM (several fold above the IC50 
[ave.~0.09 uM]) for >8 hours.  RP2D has been determined to be 480 mg bid. Among those evaluable for 
tumor response (RECIST 1.1), disease control (disease stabilization and regression) was observed in 65% 
of patients. Prolonged time to progression was observed in 46% of evaluable patients, including patients 
with CRC, head & neck, gastric, ovarian, melanoma, and breast cancer. In the subset of patients with 
CRC (N=18), disease control was seen in 67% of those evaluable.  Median progression free survival 
(PFS) and overall survival (OS) of 14 and 47 weeks, respectively, were observed in evaluable CRC 
patients.  Median OS for biomarker-positive (nuclear β-catenin and high p-STAT3) CRC patients was 53 
weeks and 54 weeks, respectively.  In this study, BBI608 has shown a favorable safety and PK profile, 
and encouraging signs of activity, particularly in CRC.  
In addition, BBI608 has been evaluated in combination therapy in the Phase Ib/II studies.  BBI608 has 
been safely combined at full dose with paclitaxel or capecitabine (BBI608-201 and BBI608-224, 
respectively), with a similar adverse event profile compared to monotherapy of either of the agents. The 
RP2D of BBI608 in combination with weekly paclitaxel or capecitabine has been determined to be 480 
mg po bid.  
Given the clinical data thus far, and the encouraging in vitro and in vivo results seen with combination of 
BBI608 with 5-FU or oxaliplatin or irinotecan or regorafenib, further evaluation of BBI608 in 
combination therapy to treat gastrointestinal malignancies is warranted.  
 
1.5 Safety and Encouraging Signs of Antitumor Activity in the BBI608-246 Study 
Since activating the BBI608-246 study, BBI608 combined with bi-weekly standard FOLFIRI with or 
without bevacizumab has been administered safely to 94 patients. The RP2D of BBI608 combined with 
FOLFIRI with or without bevacizumab was declared to be 240 mg PO BID (480 mg total daily dose). 
Combination treatment with BBI-608 and FOLFIRI with or without bevacizumab was well tolerated with 
no dose-limiting toxicity and safety profile similar to that of each regimen individually with no difference 
in safety observed with addition of bevacizumab.  Most common adverse events included Grade 1 and 2 
diarrhea, abdominal cramps, nausea, vomiting and anorexia (please see table below). Of the 65 patients 
for whom safety data is available at the clinical cut off of this application, Grade 3 AEs observed in 20 
patients included diarrhea (12), fatigue (4), dehydration (1), hyponatremia (1), hypokalemia (1), 
hypophosphatemia (1), weight loss (1) and burning in rectum (1) resolved with dose reduction and/or 
supportive care. Additional adverse events included sequelae likely secondary to GI events, such as 
fatigue and dehydration. There were no Grade 4 or 5 adverse events observed. 


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Subjects with Adverse Events Possibly Related to BBI-608 in Combination with bi-weekly 
FOLFIRI with or without Bevacizumab 
Total number of subjects with AE data:  N = 65 
 
Any 
Grade 
Grade 1 
Grade 2 
Grade 3 
System 
CTCAE 
# 
% 
# 
% 
# 
% 
# 
% 
Gastrointestinal Disorders 
Diarrhea 
55 84.6% 47 72.3% 30 46.2% 16 24.6% 
 
Nausea 
48 73.8% 41 63.1% 20 30.8% 
0 
0.0% 
 
Vomiting 
38 58.5% 29 44.6% 16 24.6% 
0 
0.0% 
 
Abdominal Pain 
31 47.7% 24 36.9% 15 23.1% 
2 
3.1% 
 
Constipation 
16 24.6% 14 21.5% 
6 
9.2% 
0 
0.0% 
 
Mucositis Oral 
11 16.9% 10 15.4% 
2 
3.1% 
0 
0.0% 
 
Flatulence 
8 
12.3% 
6 
9.2% 
2 
3.1% 
0 
0.0% 
 
Dyspepsia 
7 
10.8% 
5 
7.7% 
4 
6.2% 
0 
0.0% 
Constitutional 
Fatigue 
42 64.6% 38 58.5% 26 40.0% 
5 
7.7% 
 
Weight Loss 
12 18.5% 11 16.9% 
3 
4.6% 
1 
1.5% 
Metabolism And Nutrition Disorders 
Anorexia 
34 52.3% 28 43.1% 14 21.5% 
0 
0.0% 
 
Hypokalemia 
8 
12.3% 
6 
9.2% 
5 
7.7% 
3 
4.6% 
Neuro-Psychiatric 
Dysgeusia 
9 
13.8% 
9 
13.8% 
1 
1.5% 
0 
0.0% 
Renal And Urinary Disorders 
Urine Discoloration 
11 16.9% 11 16.9% 
0 
0.0% 
0 
0.0% 
Other 
Mucositis 
11 16.9% 
9 
13.8% 
3 
4.6% 
0 
0.0% 
 
*Events observed in 10% or more study subjects; adverse events graded using CTCAE v 4.1


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We recently reported efficacy data on 46 subjects with advanced CRC enrolled in combination with 
FOLFIRI with or without bevacizumab.  Of the heavily pretreated patients with an average of >2 
prior lines of therapy, 21 patients (46%) previously progressed on FOLFIRI with or without 
bevacizumab (O’Neil, ASCO 2016). DCR (PR+SD) was observed in 37 of 40 evaluable patients 
(93%) with PR in 13 patients (33%) (33 - 67% regression) and SD with tumor regression in 18 
patients (45%), which compare favorably with the DCR of 68% and ORR of 5.4% observed with 
FOLFIRI with bevacizumab and with the DCR of 54% and ORR of 3.9% observed with FOLFIRI 
alone (Bennouna 2013). Of 20 patients who had progressed on FOLFIRI with or without 
bevacizumab previously and were evaluable for tumor assessment, disease control (PR+SD) was 
observed in 18 patients (90%), tumor regression was observed in 15 patients (75%) of which 6 
patients achieved PR (30%). Among 14 XELIRI/FOLFIRI-refractory patients who had previously 
progressed on FOLFIRI with or without bevacizumab during or < 3 months of last dose, disease 
control (PR+SD) was observed in 12 patients (86%), tumor regression was observed in 9 patients 
(64%) of which 3 patients achieved PR (25%), confirming encouraging signs of anti-tumor activity in 
CRC patients, including FOLFIRI-refractory patients. Given the BBI608-246 clinical data seen with 
combination with BBI608 with FOLFIRI with or without bevacizumab, further evaluation of BBI608 
in combination with FOLFIRI (with bevacizumab if clinically indicated) in FOLFIRI/XELIRI-
refractory CRC patients is warranted.  
 
2 STUDY OBJECTIVES 
2.1 Primary Objectives 
The primary objective of Phase Ib of this study is: 
• 
To determine the safety, tolerability and recommended Phase 2 dose (RP2D) of BBI608 
when administered in combination with FOLFOX6 with and without bevacizumab, or 
CAPOX, or FOLFIRI with and without bevacizumab, regorafenib or irinotecan in adult 
patients with advanced gastrointestinal cancer. 
The primary objective of Phase II of this study is: 
• 
To assess the objective response rate (ORR) of BBI608 administered in combination with 
FOLFIRI (with bevacizumab if clinically indicated) in patients with FOLFIRI/XELIRI-
refractory mCRC. 
 
2.2 Secondary Objectives 
The secondary objectives of this study are: 
• 
To determine the pharmacokinetic profile of BBI608 administered in combination with 
FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without 
bevacizumab, or regorafenib. 
• 
To determine the pharmacodynamics (i.e., identify biomarkers) of BBI608 administered in 
combination with FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with 
and without bevacizumab, regorafenib or irinotecan. 


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• 
To assess the preliminary anti-tumor activity of BBI608 administered in combination with 
FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without 
bevacizumab, regorafenib or irinotecan. 
• 
To assess the disease control rate (DCR), progression-free survival (PFS), and overall 
survival (OS) of BBI608 administered in combination with FOLFIRI (with bevacizumab if 
clinically indicated) in patients with FOLFIRI/XELIRI-refractory mCRC. 
 
3 SELECTION OF STUDY POPULATION  
This study will be conducted in patients with advanced solid gastrointestinal malignancies for whom 
treatment with FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without 
bevacizumab, regorafenib or irinotecan is an appropriate treatment option in the judgment of 
physician investigators. 
The study will be conducted at sites in the United States, Canada, and Europe.  
 
3.1 Inclusion Criteria  
Each patient must meet the following criteria to be enrolled in this study. 
1. Signed written informed consent must be obtained and documented according to  
International Conference on Harmonisation (ICH)- Good Clinical Practice (GCP), the local 
regulatory requirements, and permission to use private health information in accordance with 
the Health Insurance Portability and Accountability Act (HIPAA) prior to study-specific 
screening procedures. 
2. A histologically confirmed solid tumor of the gastrointestinal tract including 
a. Advanced unresectable, metastatic or recurrent colorectal carcinoma (CRC) for 
which treatment with FOLFOX6 with or without bevacizumab, FOLFIRI with or 
without bevacizumab, CAPOX, or regorafenib would be acceptable as determined by 
the Investigator. 
i. FOLFIRI/XELIRI-refractory patients with CRC enrolling on the FOLFIRI 
(with bevacizumab if clinically indicated) study arm must have failed 
treatment with one FOLFIRI or XELIRI with or without bevacizumab 
regimen for unresectable or metastatic disease. Treatment failure is defined 
as progression of disease (clinical or radiologic) during treatment with 
FOLFIRI or XELIRI with or without bevacizumab or < 3 months after the 
last dose of treatment with FOLFIRI or XELIRI with or without 
bevacizumab.  
ii. Patients with CRC enrolling on the regorafenib arm of this study will have 
previously received at least two previous lines of therapy for advanced 
colorectal cancer, and will have previously received treatment with a 
fluoropyrimidine, oxaliplatin, and irinotecan. Patients with K-ras wild type 
tumors enrolling on the regorafenib arm will also have previously received 
either cetuximab or panitumumab. 
iii.  Advanced unresectable, metastatic or recurrent hepatocellular carcinoma for 
which treatment with FOLFOX6 or CAPOX would be acceptable as 
determined by the Investigator. 


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iv. Advanced unresectable, metastatic or recurrent pancreatic adenocarcinoma 
for which treatment with FOLFOX6, CAPOX, FOLFIRI or irinotecan would 
be acceptable as determined by the Investigator. 
b.  Advanced unresectable, metastatic or recurrent cholangiocarcinoma for which 
treatment with FOLFOX6 or CAPOX would be acceptable as determined by the 
Investigator.  
i. Advanced unresectable, metastatic, or recurrent gastric, GEJ or esophageal 
adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI or 
irinotecan would be acceptable as determined by the Investigator. 
  
c. Patients may be treatment-naïve, or may have received standard chemotherapy; 
including regimens containing a fluoropyrimidine, or oxaliplatin, or irinotecan, or 
regorafenib, or bevacizumab. 
3. ≥18 years of age.  
4. Karnofsky performance status score ≥70% (Appendix E).  
5. Male or female patients of child-producing potential agree to use contraception or avoidance 
of 
pregnancy 
measures 
during 
the 
study 
and 
for 
30 
days 
after 
the 
last  
BBI608 dose.  
6. Females of childbearing potential have a negative serum pregnancy test. 
7. Aspartate transaminase (AST) level <2.5 x upper limit of normal (ULN) and alanine 
transaminase (ALT) ≤2.5 × upper limit of normal (ULN).  For patients with liver metastases, 
AST <3.5 ULN, and AST <3.5 ULN may be enrolled if agreed upon by the investigator and 
medical monitor for the sponsor. 
8. Hemoglobin (Hgb) ≥10 g/dl. 
9. Total bilirubin level ≤1.5 × ULN. 
10. Creatinine level ≤1.5 × ULN or creatinine clearance >60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal (as determined by Cockroft-Gault equation). 
11. Absolute neutrophil count ≥1.5 x 109/L. 
12. Platelets ≥100 x 109/L. 
13. Life expectancy estimated at ≥3 months. 
3.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
1. Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 7 
days of the first dose of BBI608.  Patients may begin BBI608 on a date determined by the 
investigator and medical monitor for the sponsor after a minimum of 7 days since last 
receiving anti-cancer treatment, provided that all treatment-related AEs have resolved or have 
been deemed irreversible. 
2. Major surgery within 4 weeks prior to first dose. 
3. Any known untreated brain metastases.  Treated subjects must be stable for 4 weeks after 
completion of that treatment, with image documentation required.  Patients must have no 


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clinical symptoms from brain metastases and must be either off steroids or on a stable dose of 
steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal 
metastases are excluded, even if treated. 
4. Pregnant or breastfeeding.  
5. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, 
prevent absorption of an orally available agent (e.g., Crohn’s disease, ulcerative colitis, 
extensive gastric resection and small intestinal resection).   
6. Unable or unwilling to swallow BBI608 capsules or tablets daily. 
7. Prior treatment with BBI608.   
8. 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, 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. 
9. For patients to be treated with a regimen containing 5-fluorouracil/leucovorin: 
a. Known hypersensitivity to 5-fluorouracil/leucovorin 
b. Known dihydropyrimidine dehydrogenase (DPD) deficiency 
10. For patients to be treated with a regimen containing capecitabine: 
a. Known hypersensitivity to capecitabine 
b. Known dihydropyrimidine dehydrogenase (DPD) deficiency 
c. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal 
Investigator, prevent absorption of an orally available agent  
11. For patients to be treated with a regimen containing oxaliplatin: 
a. Neurosensory neuropathy ≥ grade 2 at baseline 
b. Known hypersensitivity to oxaliplatin or other platinum containing compounds 
12. For patients to be treated with a regimen containing irinotecan: 
a. Known hypersensitivity to irinotecan 
b. Abnormal glucuronidation of bilirubin 
13. For patients to be treated with a regimen containing bevacizumab: 
a. 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 
b. 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) 
c. History of arterial thrombotic or embolic events (within 6 months prior to study 
entry) 


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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). 
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) 
14. For patients to be treated with a regimen containing regorafenib: 
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)  
c. Interstitial lung disease with ongoing signs and symptoms at the time of screening 
d. History of HIV infection or chronic hepatitis B or C (hepatitis B is allowed if no 
active replication is present; hepatitis C is allowed if no antiviral treatment is 
required)  
e. Active clinically serious infections  
f. History of arterial or embolic events (within 6 months prior to study entry) 
g. Liver cirrhosis ≥ Child-Pugh class B with uncontrolled ascites (defined as not easily 
controlled with diuretic or paracentesis treatment)  
h. History of RPLS 
i. 
Ongoing serious, non-healing wound, ulcer, or bone fracture  
j. 
Evidence of bleeding diathesis or a clinically significant coagulopathy (>CTCAE 
Grade 3 within 4 weeks prior to the start of study)  
k. Renal failure requiring hemo- or peritoneal dialysis 
l. 
Persistent proteinuria of CTCAE grade 3 (>3.5g/24 hours) 


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m. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal 
Investigator, prevent absorption of an orally available agent  
n. Known hypersensitivity to regorafenib 
 
3.3 Number of Patients 
The exact number of patients estimated for this trial is dependent on the number of patient cohorts 
investigated based on the toxicity encountered.  It is expected that, for each combination arm (except 
for irinotecan combination study arm for which RP2D in combination with BBI608 has already been 
established)*, approximately 9 to 12 patients will be enrolled in the dose escalation part of the study. 
Up to an additional 15 patients may be enrolled at RP2D in each arm. An additional 20 evaluable 
subjects will be enrolled on the hepatocellular carcinoma, cholangiocarcinoma, and gastric/GEJ, 
esophageal or pancreatic adenocarcinoma disease cohorts.   
Safety of BBI608 at 480 mg by mouth twice daily (960 mg total daily dose) will be evaluated in each 
combination arm, including after RP2D establishment in that combination. DLT assessment will be 
performed as above with 6 patients enrolled at the dose of 480 mg by mouth twice daily (960 mg total 
daily dose). Up to an additional 15 evaluable patients may be enrolled in each cohort at the dose of 
480 mg by mouth twice daily (960 mg total daily dose) as long as <1 of 6 patients experience a DLT 
at the 480 mg by mouth twice daily dose level (960 mg total daily dose).  
Up to an additional 50 evaluable FOLFIRI/XELIRI-refractory CRC patients will be enrolled on the 
FOLFIRI (with bevacizumab if clinically indicated) study arm as an expansion cohort. FOLFIRI-
refractory CRC patients will have failed treatment with FOLFIRI with or without bevacizumab 
regimen with failure defined as progression of disease during or <3 months after the last dose of 
FOLFIRI/XELIRI with or without bevacizumab.  
 
 


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4 INVESTIGATIONAL PLAN 
4.1 Overall Study Design 
This is an open-label, Phase 1b, dose escalation study of oral BBI608 administered to patients with 
advanced gastrointestinal malignancy in combination with FOLFOX6 with and without bevacizumab, 
or CAPOX, or FOLFIRI with and without bevacizumab, regorafenib or irinotecan.  The study is 
designed to explore the safety, tolerability and pharmacokinetics of BBI608, and to define a 
recommended Phase 2 dose of BBI608 in combination with each one of the above regimens (except 
for irinotecan study arm for which RP2D in combination with BBI608 has been established). 
Initially, 3 patients will be enrolled in each combination arm (except for the irinotecan study arm for 
which enrollment will begin with the expansion phase skipping DLT period assessment being that 
RP2D for BBI608 in combination with irinotecan has been established at the time of this 
amendment*) at a BBI608 dose level of 240 mg twice daily (480 mg total daily dose—Cohort I).  If 0 
out of 3 patients experience a DLT, then the BBI608 dose will be escalated to 480 mg twice daily 
(960 mg total daily dose—Cohort II) and 6 patients will be enrolled at this dose level. If 1 out of 3 
patients in the 240 mg by mouth twice daily cohort experience a DLT, then an additional 3 patients 
will be enrolled in that arm.  If a DLT occurs in ≥2 of the 6 patients in an arm, then the BBI608 dose 
will be reduced to 160 mg twice daily (320 mg total daily dose—Cohort Ib) and 6 patients will be 
enrolled at this does level.  
If <1 of 6 patients experience a DLT at the 240 mg by mouth twice daily dose level, then BBI608 
dose will be escalated to 480 mg by mouth twice daily (960 mg total daily dose) and 6 patients will be 
enrolled at this dose level. If ≤1 out of 6 patients experiences a DLT at 480 mg by mouth twice daily, 
this dose level will be considered the Recommended Phase 2 Dose (RP2D) for BBI608 in that 
combination.  
If ≥2 out of 6 patients experience a DLT at 480 mg by mouth twice daily, then RP2D will be declared 
as the next lowest dose level at which ≤1 out of 6 patients experiences a DLT.  
Cycles of therapy will consist of the patient taking BBI608 daily in combination therapy for 28 days.  
Tumor assessments will be performed every two cycles (eight weeks), or as otherwise clinically 
indicated. 
 
 


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Dose escalation scheme for BBI608 
Cohort 
Total Daily Dosea (mg) 
Number of Patients 
I 
480 mg 
3 b,c 
Ib 
320 mg 
3 b,d 
II 
960 mg 
6 
a. Daily dose must be taken one hour prior to or two hours after meals 
b If a BBI608-related DLT is seen in a 3 patient cohort  an additional 3 patients will be 
enrolled at the same dose 
cIf ≥2 of 6 patients experience a DLT, then BBI608 dose will be reduced to 160 mg 
twice daily (total daily dose of 320 mg—Cohort Ib) and 6 patients will be enrolled at 
this dose level.  
dIf ≥2 patients experience a DLT at this dose level, the arm will be closed to accrual. 
 
The recommended phase 2 dose (RP2D) for a given combination arm is defined as the dose level at 
which no more than one patient with DLT is observed among six patients for each combination.  
Once the RP2D has been reached for a given combination arm based on DLT assessment rules 
outlined above, up to 15 additional evaluable patients may be enrolled at RP2D.  If a patient drops-
out, another patient may be enrolled such that there are 15 evaluable patients available for analysis. 
An additional 20 evaluable subjects will be enrolled on the hepatocellular carcinoma, 
cholangiocarcinoma, gastric/GEJ, esophageal or pancreatic adenocarcinoma disease cohorts.  Up to 
an additional 50 evaluable FOLFIRI/XELIRI-refractory CRC patients will be enrolled on the 
FOLFIRI (with bevacizumab if clinically indicated) study arm as an expansion cohort.   
 
 
 


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Number of Subjects with 
DLT at a Given Dose Level 
for a Given Combination 
Arm 
 
Escalation Decision Rule 
 
0 out of 3 
 
Enter 3 subjects at the next dose level 
 
>2 
 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional subjects will be entered at 
the next lower dose level if only 3 subjects were treated 
previously at that dose. 
 
1 out of 3 
 
Enter at least 3 more subjects at this dose level. 
• 
If 0 of these 3 subjects experience DLT, proceed to the 
next dose level. 
• 
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
subjects will be entered at the next lower dose level if 
only 3 subjects were treated previously at that dose. 
 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
 
This is the recommended phase 2 dose for this combination 
arm.  Once the RP2D has been defined based on DLT 
assessment rules outlined in this section, up to 15 additional 
subjects will be enrolled followed by an additional 20 
evaluable patients in each of the following groups: HCC, 
cholangiocarcinoma, gastric/GEJ, esophageal or pancreatic 
adenocarcinoma. 
Up 
to 
an 
additional 
50 
evaluable 
FOLFIRI/XELIRI-refractory CRC patients will be enrolled on 
the FOLFIRI (with bevacizumab if clinically indicated) 
study arm as an expansion cohort.   
 
4.2 Rationale for Study Design  
Considerable data has been collected from the Phase I monotherapy study of BBI608 (protocol 
BBI608-101) as well as phase 1b/II studies (BBI608-201, BBI608-224) conducted in advanced 
oncology patients who have failed multiple previous regimens.BBI608 has shown a favorable safety 
and PK profile, and encouraging signs of activity.   Combination of cancer stem cell therapeutics with 
chemotherapy would allow simultaneous inhibition of cancer stem cells as well as non-stem tumor 
bulk cells. Given the clinical data thus far, and the encouraging in vitro and in vivo results seen with 
combination of BBI608 with 5-FU or oxaliplatin or irinotecan or regorafenib, further evaluation of 
BBI608 in combination therapy to treat gastrointestinal malignancies is warranted. 
 
4.3 Selection of Dose 
Dose escalation for BBI608 has been successfully conducted from 20 to 2000 mg total daily dose. 
MTD was not reached and RP2D was determined based on pharmacokinetics. Adverse events 
observed in the BBl608 monotherapy phase I trial have been generally mild (Grade 1-2) with the 
most common being diarrhea, nausea, anorexia and fatigue.  Grade 3 events include fatigue and 
diarrhea. No bone marrow suppression or neuropathy was observed. 


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In phase 1b/II studies, BBI608 has been successfully combined at full dose (480 mg twice daily) with 
weekly paclitaxel or capecitabine, without any signs of adverse effects that differ from either agent 
administered as monotherapy.  
Dosing of BBI608 in each combination arm of this trial will be initiated at 480 mg/day, which is 50% 
of the monotherapy RP2D for BBI608, and is also 50% of the RP2D of BBI608 in combination with 
weekly paclitaxel or capecitabine.  Dosing of BBI608 in the FOLFIRI/XELIRI-refractory CRC 
expansion cohorts will be at 480 mg/day. 
 
4.4 Criteria for Dose Escalation and Determination of Dose-Limiting Toxicity 
Patients must have been treated with both BBI608 and the designated combination regimen to be 
evaluable for Dose-Limiting Toxicity (DLT). Patients evaluable for dose escalation are defined as 
having been exposed to at least 28 days of continuous daily administration of BBI608, starting from 
Cycle 1 Day 1 or having had a protocol defined DLT at any time within this period.   Based on the 
tolerability and safety of evaluable patients, enrollment at the next dose level and/or enrollment of 
additional patients into the ongoing cohort for each combination arm will occur according to criteria 
described below:  
• 
If zero treated patients experience a BBI608-related DLT (defined below) by Day 28 of Cycle 
1, then dose escalation will occur. 
• 
If one treated patient experiences a BBI608-related DLT by Day 28 of Cycle 1, then an 
additional three patients will be enrolled for a total of six patients treated at the same dose 
level.  Escalation will occur if no additional DLTs are seen in that cohort (i.e. one out of six 
patients)  
• 
If two or more treated patients at a dose level experience a BBI608-related DLT by Day 28 of 
Cycle 1, dose escalation will stop and this dose level will be considered the maximally 
administered dose. Three (3) additional patients will be entered at the next lower dose level if 
only 3 patients were treated previously at that dose. 
• 
The recommended phase 2 dose (RP2D) for a given combination arm is defined as the dose 
level at which no more than one patient with DLT is observed among six patients for each 
combination 
The BBI medical Monitor and Principal Investigator will review all significant BBI608-related 
toxicities to determine if the dose escalation schedule requires modification.  Intermediate doses may 
be assigned to a cohort after agreement between the BBI Medical Monitor and the Principal 
Investigator.  
 
4.5 Dose-Limiting Toxicity 
Dose-limiting toxicity is defined by the occurrence of any of the following toxicities possibly or 
probably related to BBI608 or BBI608 in combination with FOLFOX6 with and without 
bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, regorafenib or irinotecan, 
which includes all following toxicities unless there is a clear alternative explanation.  DLT will be 
scored during the first cycle of BBI608 treatment.  
• 
Grade 4 hematological toxicity. In addition, Grade 3 thrombocytopenia associated with a 
clinically significant bleeding event will be considered a DLT 
• 
Grade 3 or 4 non-hematological toxicity, except:  


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o Grade 3 nausea/vomiting/anorexia, diarrhea, or fatigue will be considered a DLT 
only if it persists for 3 days despite optimal medical management 
o Alopecia will not be considered a DLT 
• 
Any other toxicity that in the view of the Principal Investigator represents a clinically 
significant hazard to the patient, including delays or omissions of the backbone chemotherapy 
regimen. 
Whether a DLT has occurred will be assessed during the 28 days of Cycle 1.  DLT will be determined 
from adverse events, changes from baseline in physical examination findings and laboratory 
parameters.  The incidence of adverse events and DLTs will be evaluated for each combination arm 
and for all patients (except for the irinotecan combination arm for which RP2D in combination with 
BBI608 has been established).   
 
 
4.6 Study Duration  
Patients will receive treatment with BBI608 until progression of disease (clinical or radiological), 
unacceptable toxicity or another discontinuation criterion is documented (see Section 5.7).  It is 
expected that most patients will receive between one and four cycles of BBI608 for a treatment period 
of 4 to 16 weeks.  
 
 
5 STUDY VISITS 
 
5.1 Overview 
Study Visits will consist of a Pre-Study Evaluation, during which the patient is evaluated to determine 
suitability for entry into the study, Weekly Evaluations during which the patient is regularly evaluated 
during conduct of the study, Monthly Evaluations, which begin after the completion of Cycle 1, and 
an End-of-Study Evaluation (See APPENDICES A through D for schedules of Assessments for each 
study arm).  
Following the Pre-Study Evaluation and a determination by a Principal Investigator that the patient 
meets all inclusion/exclusion criteria and signs the informed consent, the patient will be considered 
enrolled in the study.   
 
5.2 Informed Consent 
Patients who agree to participate will sign the approved informed consent and will be provided a copy 
of the signed document.   
Informed consent may be obtained within approximately one month prior to the first dose of BBI608.  
All screening procedures should be performed within 9 days of the first dose of BBI608 (unless 
otherwise noted).   
 
5.3 Pre-Study Evaluations (Baseline) 


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After written informed consent is obtained according to ICH-GCP and local regulations, the patient 
will be evaluated for inclusion and exclusion criteria according to the eligibility criteria listed in 
Section 3.   
The following will be evaluated and documented within seven days prior to first dose of BBI608: 
• 
Medical history 
• 
Physical examination 
• 
Karnofsky performance status score (see APPENDIX E) 
• 
Vital signs (weight, temperature, blood pressure, height, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3)  
• 
Serum pregnancy test (if applicable) 
• 
Tumor markers if applicable 
• 
Record concomitant medication 
• 
Baseline tumor biopsy, if applicable (can be scheduled for any time prior to first dose of 
BBI608 - see Section 6.6); additionally, archival tissue will be obtained per Appendix G once 
the patient has been enrolled. 
• 
12-lead electrocardiogram (ECG) 
• 
Tumor measurement and staging [computed tomography (CT) scan or magnetic resonance 
imaging (MRI) scan acceptable]* 
 
*All CT and MRI scans can be used for baseline assessment if they were performed within three 
weeks of the first scheduled dose of BBI608.   
 
5.4 On-Study Assessments  
5.4.1 
FOLFOX6 Arm 
5.4.1.1  Week 0 (Day [-] 5) 
A Day [-] 5 visit should ONLY occur during the first cycle of BBI608 administration. Patients who 
meet all inclusion and exclusion criteria will have the following assessments: 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
12-lead electrocardiogram (ECG)* 
• 
Record concomitant medication 
• 
Dispense BBI608 (5 day supply plus 2 extra days) 
 
* The 12-lead electrocardiogram on Cycle 1 Day [-5] should be obtained two hours after first 
BBI608 has been administered. 
5.4.1.2 Cycle 1, Day 1 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 


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• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Dispense BBI608 (28 day supply) 
• 
FOLFOX6 regimen, IV infusion starting 3 hours after the first morning dose of BBI608* 
• 
Blood samples for pharmacokinetics, red blood cell pellet Cycle 1 ONLY (see APPENDIX 
F) 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of FOLFOX therapy is 
required only during Cycle 1, in order to standardize PK interpretation. Following completion of 
Cycle 1, the first daily administration of BBI608 should precede the administration of FOLFOX by 1-
4 hours. 
 
5.4.1.3 Cycle 1, Day 15 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
FOLFOX6 regimen, IV infusion starting 3 hours after the first morning dose of BBI608* 
• 
Blood samples for pharmacokinetics, Cycle 1 ONLY (see APPENDIX F) 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of FOLFOX therapy is 
required only during Cycle 1, in order to standardize PK interpretation. Following completion of 
Cycle 1, the first daily administration of BBI608 should precede the administration of FOLFOX by 1-
4 hours. 
 
5.4.1.4 Cycle 2 and Beyond 
Day 1 
• 
Physical examination  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3) 
• 
Tumor markers (if applicable) 
• 
Tumor biopsy (for Cycle 2 only, if applicable ) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
FOLFOX6 regimen, IV infusion starting 1-4 hours after the first morning dose of BBI608 
• 
Dispense BBI608 (28 day supply plus 2 days) 
 
Day 15 


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• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Karnofsky performance status score 
• 
Hematology (see Section 6.3) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
FOLFOX6 regimen, IV infusion starting 1-4 hours after the first morning dose of BBI608 
 
5.4.2 
FOLFOX6 with Bevacizumab Arm 
5.4.2.1  Week 0 (Day [-] 5) 
 
A Day [-] 5 visit should ONLY occur during the first cycle of BBI608 administration. Patients who 
meet all inclusion and exclusion criteria will have the following assessments: 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
12-lead electrocardiogram (ECG)* 
• 
Record concomitant medication 
• 
Dispense BBI608 (5 day supply plus 2 extra days) 
 
* The 12-lead electrocardiogram on Cycle 1 Day [-5] should be obtained two hours after first BBI608 
has been administered. 
5.4.2.2 Cycle 1, Day 1 
The patient will have the following assessments:  
• 
Karnofsky performance status 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Dispense BBI608 (28 day supply) 
• 
FOLFOX6 plus bevacizumab regimen, IV infusion starting 3 hours after the first morning 
dose of BBI608* 
• 
Blood samples for pharmacokinetics, red blood cell pellet Cycle 1 ONLY (see APPENDIX 
F) 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of FOLFOX6 plus 
bevacizumab therapy is required only during Cycle 1, in order to standardize PK interpretation. 
Following completion of Cycle 1, the first daily administration of BBI608 should precede the 
administration of FOLFOX6 plus bevacizumab by 1-4 hours. 
 
5.4.2.3 Cycle 1, Day 15 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 


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• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
FOLFOX6 plus bevacizumab regimen, IV infusion starting 3 hours after the first morning 
dose of BBI608 
• 
Blood samples for pharmacokinetics, Cycle 1 ONLY (see APPENDIX F) 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of FOLFOX6 plus 
bevacizumab therapy is required only during Cycle 1, in order to standardize PK interpretation. 
Following completion of Cycle 1, the first daily administration of BBI608 should precede the 
administration of FOLFOX6 plus bevacizumab by 1-4 hours. 
 
5.4.2.4 Cycle 2 and Beyond 
Day 1 
• 
Physical examination  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3) 
• 
Tumor markers (if applicable) 
• 
Tumor biopsy (for Cycle 2 only, if applicable)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
FOLFOX6 plus bevacizumab regimen, IV infusion starting 1-4 hours after the first morning 
dose of BBI608 
• 
Dispense BBI608 (28 day supply plus 2 days) 
Day 15 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Karnofsky performance status score 
• 
Hematology (see Section 6.3) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
FOLFOX6 plus bevacizumab regimen, IV infusion starting 1-4 hours after the first morning 
dose of BBI608 
 
5.4.3 
CAPOX Arm 
5.4.3.1 Week 0 (Day [-] 5) 
A Day [-] 5 visit should ONLY occur during the first cycle of BBI608 administration. Patients who 
meet all inclusion and exclusion criteria will have the following assessments: 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
12-lead electrocardiogram (ECG)* 
• 
Record concomitant medication 


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• 
Dispense BBI608 (5 day supply plus 2 extra days) 
 
* The 12-lead electrocardiogram on Cycle 1 Day [-5] should be obtained two hours after first BBI608 
has been administered. 
5.4.3.2 Cycle 1, Day 1 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Dispense BBI608 (28 day supply) 
• 
Dispense capecitabine supply for Cycle 1* 
• 
CAPOX  regimen, with oral capecitabine administration and oxaliplatin IV infusion starting 3 
hours after the first morning dose of BBI608** 
• 
Blood samples for pharmacokinetics, red blood cell pellet Cycle 1 ONLY (see APPENDIX 
F) 
 
*Capecitabine must be administered starting in the morning of Cycle 1, Day 1. Following completion 
of Cycle 1, capecitabine administration at the begining of a new 3-week cycle may start with evening 
dosing, at the discretion of the Investigator. 
 
** A 3 hour interval between the first daily dose of BBI608 and the administration of oxaliplatin 
and/or capecitabine is required on Days 1, 2, 22 and 23 of Cycle 1 only, in order to standardize PK 
interpretation. On all other days, the first daily administration of BBI608 should precede the 
administration of oxaliplatin and/or capecitabine by 1-4 hours. 
 
 
5.4.3.3 Cycle 1, Day 22 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
CAPOX  regimen, with oral capecitabine administration and oxaliplatin IV infusion starting 
about 3 hours after the first morning dose of BBI608* 
• 
Blood samples for pharmacokinetics, Cycle 1 ONLY (see APPENDIX F) 
 
* A 3 hour interval between the first daily dose of BBI608 and the administration of oxaliplatin 
and/or capecitabine is required on Days 1, 2, 22 and 23 of Cycle 1 only, in order to standardize PK 
interpretation. On all other days, the first daily administration of BBI608 should precede the 
administration of oxaliplatin and/or capecitabine by 1-4 hours. 


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5.4.3.4 Cycle 2 and Beyond 
Day 1 
• 
Physical examination  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3) 
• 
Tumor markers (if applicable) 
• 
Tumor biopsy (for Cycle 2 only, if applicable) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
CAPOX regimen, with oral capecitabine administration and oxaliplatin IV infusion starting 
1-4 hours after the first morning dose of BBI608 
• 
Dispense BBI608 (28 day supply plus 2 days) 
• 
Dispense capecitabine supply for the given 28 Day Cycle  
 
NOTE: Due to the 3 week nature of CAPOX cycles, the weeks that capecitabine and the day(s) 
that oxaliplatin are administered during the 28-day study cycle will vary from cycle to cycle. 
 
5.4.4 
FOLFIRI Arm 
5.4.4.1 Week 0 (Day [-] 5) 
A Day [-] 5 visit should ONLY occur during the first cycle of BBI608 administration. Patients who 
meet all inclusion and exclusion criteria will have the following assessments: 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
12-lead electrocardiogram (ECG)* 
• 
Record concomitant medication 
• 
Dispense BBI608 (5 day supply plus 2 extra days) 
 
* The 12-lead electrocardiogram on Cycle 1 Day [-5] should be obtained two hours after first BBI608 
has been administered. 
5.4.4.2 Cycle 1, Day 1 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Dispense BBI608 (28 day supply) 


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June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 36 
• 
FOLFIRI regimen, IV infusion starting 3 hours after the first morning dose of BBI608* 
• 
Blood samples for pharmacokinetics, red blood cell pellet Cycle 1 ONLY (see APPENDIX 
F) 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of FOLFIRI therapy is 
required only during Cycle 1, in order to standardize PK interpretation. Following completion of 
Cycle 1, the first daily administration of BBI608 should precede the administration of FOLFIRI by 1-
4 hours. 
 
5.4.4.3 Cycle 1, Day 15 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
FOLFIRI regimen, IV infusion starting 3 hours after the first morning dose of BBI608* 
• 
Blood samples for pharmacokinetics, Cycle 1 ONLY (see APPENDIX F) 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of FOLFIRI therapy is 
required only during Cycle 1, in order to standardize PK interpretation. Following completion of 
Cycle 1, the first daily administration of BBI608 should precede the administration of FOLFIRI by 1-
4 hours. 
 
5.4.4.4 Cycle 2 and Beyond 
Day 1 
• 
Physical examination  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3) 
• 
Tumor markers (if applicable) 
• 
Tumor biopsy (for Cycle 2 only, if applicable) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
FOLFIRI regimen, IV infusion starting 1-4 hours after the first morning dose of BBI608 
• 
Dispense BBI608 (28 day supply plus 2 days) 
Day 15 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Assess adverse events (AE) 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
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Page 37 
• 
Record concomitant medication 
• 
FOFLIRI regimen, IV infusion starting 1-4 hours after the first morning dose of BBI608 
 
5.4.5 
FOLFIRI with Bevacizumab Arm 
5.4.5.1 Week 0 (Day [-] 5) 
A Day [-] 5 visit should ONLY occur during the first cycle of BBI608 administration. Patients who 
meet all inclusion and exclusion criteria will have the following assessments: 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
12-lead electrocardiogram (ECG)* 
• 
Record concomitant medication 
• 
Dispense BBI608 (5 day supply plus 2 extra days) 
 
* The 12-lead electrocardiogram on Cycle 1 Day [-5] should be obtained two hours after first BBI608 
has been administered. 
 
5.4.5.2 Cycle 1, Day 1 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Dispense BBI608 (28 day supply) 
• 
FOLFIRI plus bevacizumab regimen, IV infusion starting about 3 hours after the first 
morning dose of BBI608* 
• 
Blood samples for pharmacokinetics, red blood cell pellet Cycle 1 ONLY (see APPENDIX 
F) 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of FOLFIRI plus 
bevacizumab therapy is required only during Cycle 1, in order to standardize PK interpretation. 
Following completion of Cycle 1, the first daily administration of BBI608 should precede the 
administration of FOLFIRI plus bevacizumab by 1-4 hours. 
 
5.4.5.3 Cycle 1, Day 15 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 38 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
FOLFIRI plus bevacizumab regimen, IV infusion starting about 3 hours after the first 
morning dose of BBI608* 
• 
Blood samples for pharmacokinetics, Cycle 1 ONLY (see APPENDIX F) 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of FOLFIRI plus 
bevacizumab therapy is required only during Cycle 1, in order to standardize PK interpretation. 
Following completion of Cycle 1, the first daily administration of BBI608 should precede the 
administration of FOLFIRI plus bevacizumab by 1-4 hours. 
 
5.4.5.4 Cycle 2 and Beyond 
Day 1 
• 
Physical examination  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3) 
• 
Tumor markers (if applicable) 
• 
Tumor biopsy (for Cycle 2 only, if applicable) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
FOLFIRI plus bevacizumab regimen, IV infusion starting 1-4 hours after the first morning 
dose of BBI608 
• 
Dispense BBI608 (28 day supply plus 2 days) 
Day 15 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
FOFLIRI plus bevacizumab regimen, IV infusion starting 1-4 hours after the first morning 
dose of BBI608 
 
5.4.6 
Regorafenib Arm 
5.4.6.1 Week 0 (Day [-] 5) 
A Day [-] 5 visit should ONLY occur during the first cycle of BBI608 administration. Patients who 
meet all inclusion and exclusion criteria will have the following assessments: 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
12-lead electrocardiogram (ECG)* 
• 
Record concomitant medication 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 39 
• 
Dispense BBI608 (5 day supply plus 2 extra days) 
 
* The 12-lead electrocardiogram on Cycle 1 Day [-5] should be obtained two hours after first BBI608 
has been administered. 
5.4.6.2 Cycle 1, Day 1 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Dispense BBI608 (28 day supply) 
• 
Administer regorafenib about 3 hours after the first morning dose of BBI608* 
• 
Dispense regorafenib (supply for 21 days out of 28 day cycle)** 
• 
Blood samples for pharmacokinetics, red blood cell pellet Cycle 1 ONLY (see APPENDIX 
F) 
 
* A 3 hour interval between the first daily dose of BBI608 and the administration of regorafenib is 
required on Days 1, 2, 15 and 16 of Cycle 1 only, in order to standardize PK interpretation. On all 
other days, the first daily administration of BBI608 should precede the administration of regorafenib 
by 1-4 hours. 
 
 
5.4.6.3 Cycle 1, Day 15 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Administer regorafenib about 3 hours after the first morning dose of BBI608* 
• 
Blood samples for pharmacokinetics, Cycle 1 ONLY (see APPENDIX F) 
 
* A 3 hour interval between the first daily dose of BBI608 and the administration of regorafenib is 
required on Days 1, 2, 15 and 16 of Cycle 1 only, in order to standardize PK interpretation. On all 
other days, the first daily administration of BBI608 should precede the administration of regorafenib 
by 1-4 hours. 
 
5.4.6.4 Cycle 2 and Beyond 
Day 1 
• 
Physical examination  
• 
Karnofsky performance status score 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 40 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3) 
• 
Tumor markers (if applicable) 
• 
Tumor biopsy (for Cycle 2 only, if applicable) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Dispense BBI608 (28 day supply plus 2 days) 
• 
Dispense regorafenib (supply for 21 days out of 28 day cycle) 
 
5.4.7 
Irinotecan Arm 
5.4.7.1 Week 0 (Day [-] 5) 
A Day [-] 5 visit should ONLY occur during the first cycle of BBI608 administration. Patients who 
meet all inclusion and exclusion criteria will have the following assessments: 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
12-lead electrocardiogram (ECG)* 
• 
Record concomitant medication 
• 
Dispense BBI608 (5 day supply plus 2 extra days) 
 
* The 12-lead electrocardiogram on Cycle 1 Day [-5] should be obtained two hours after first BBI608 
has been administered. 
5.4.7.2 Cycle 1, Day 1 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Dispense BBI608 (28 day supply) 
• 
Irinotecan IV infusion starting 1-4 hours after the first morning dose of BBI608 
 
5.4.7.3 Cycle 1, Day 15 
The patient will have the following assessments:  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Irinotecan IV infusion starting 1-4 hours after the first morning dose of BBI608 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 41 
 
5.4.7.4 Cycle 2 and Beyond 
Day 1 
• 
Physical examination  
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry (see Section 6.3) 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3) 
• 
Tumor markers (if applicable) 
• 
Tumor biopsy (for Cycle 2 only, if applicable) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Irinotecan IV infusion starting 1-4 hours after the first morning dose of BBI608 
• 
Dispense BBI608 (28 day supply plus 2 days) 
Day 15 
• 
Karnofsky performance status score 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Assess adverse events (AE) 
• 
Record concomitant medication 
• 
Irinotecan IV infusion starting 1-4 hours after the first morning dose of BBI608 
• 
 
 
5.5 Tumor Evaluation Visits 
Disease status and tumor response will be assessed at eight-week intervals until objective disease 
progression, or as clinically indicated.  Standard imaging studies will be performed according to 
institutional procedures.  Tumor response will be evaluated using the guidelines for Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) outlined in Section 9.  De-identified radiologic 
image dictation report as well as de-identified copies of the radiologic images for independent review 
may be requested in cases where radiologic assessment is in question.  However, the study Case 
Report Forms (CRFs) will include relevant lesion measurements as determined by the study site.  
 
Patients will have confirmatory radiographic scanning within approximately 4 weeks of initial results 
of partial or complete response (PR or CR) according to RECIST 1.1. 
Once clinical or radiological progression of disease during BBI608 therapy is documented, patients 
must be taken off treatment and may receive any therapy as determined by their treating physician.   
5.6 End of Study Evaluation 
All patients will be followed for a minimum of 30 days after the last dose of BBI608.  If a patient is 
removed from the study due to drug-related adverse events, the patient will be followed until 
resolution of any drug-related AE occurring during the study or within 30 days of the last BBI608 
dose, or for 30 days, whichever is longer.  In the presence of toxic effects, follow-up visits will be 
required every four weeks until all study related toxicities have resolved to baseline (or < Common 
Terminology Criteria for Adverse Events [CTCAE] Grade 1), stabilized or are deemed irreversible.   


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
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The following assessments will be made during the end of study visit: 
• 
Physical examination 
• 
Karnofsky performance status score 
• 
Vital signs  (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Biochemistry 
• 
Urinalysis including fractional excretion of sodium phosphate (see Section 6.3) 
• 
12-lead ECG 
• 
Tumor marker, if applicable 
• 
Tumor measurement and staging if applicable 
• 
Assess adverse events 
• 
Record concomitant medications 
Patients will be followed for Overall Survival. 
5.7 Discontinuation from Study 
Patients will be removed from the study at any time if they meet any of the following criteria: 
• 
Documented radiologic or clinical progression of disease 
• 
Noncompliance with any part of the study, as evaluated by the Principal Investigator and 
Medical Monitor 
• 
Withdrawal of consent 
• 
Investigator decision 
• 
Lost to Follow-up 
• 
Death  
• 
Clinically unacceptable toxicities despite optimal treatment or dose reduction 
• 
Pregnancy 
 
6 STUDY PROCEDURES 
6.1 Medical History 
Medical history will include, but is not limited to, the following: 
• 
Demography: date of birth, sex, ethnic origin, height, and weight 
• 
Clinically significant prior diagnoses, surgeries, and current medications 
• 
Prior cancer history, current cancer diagnosis, tumor stage at time of diagnosis and screening, 
KRAS, NRAS, BRAF and MSI mutation status, previous chemotherapy, including dates and 
duration of treatment, previous radiation therapy, including anatomic site, dose and date of 
treatment 
Prior records, radiology reports, radiology imaging, or procedure notes may be required in order to 
verify components of study patient history. 
 
6.2 Physical Examination 
Complete physical examination including height, weight, blood pressure, heart rate, respiratory rate, 
temperature (oral, axillary or tympanic) and Karnofsky performance status score. 
 


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6.3 Clinical Laboratory Tests 
Safety laboratory determinations will include hematology, blood chemistry, and urinalyses.  All 
laboratory tests required during the study must be obtained at a primary laboratory designated by the 
Principal Investigator.   
• 
Hematology: CBC including hemoglobin, white blood cell count with 5-part differential, 
platelets 
• 
Biochemistry: electrolytes (sodium, potassium, and chloride), HCO2, calcium, phosphorus, 
magnesium, total protein, albumin, glucose, and serum creatinine, blood urea nitrogen 
(BUN), AST, ALT, lactate dehydrogenase (LDH), alkaline phosphatase, total and direct 
bilirubin, and uric acid 
• 
Routine urinalysis: dipstick including protein, specific gravity, glucose and blood as well as 
fractional excretion of sodium phosphate 
• 
Serum pregnancy test for female patients of childbearing potential 
 
6.4 Pharmacokinetic Assessments  
Blood samples for the PK of BBI608 will be collected from all treated patients except for patients 
enrolled on Arm G (irinotecan). Collection, storage, and shipping of PK samples will be performed as 
described APPENDIX F: Pharmacokinetic Studies. 
   
6.5 Pharmacodynamic Assessments  
Pre-clinical and clinical studies conducted by BBI have identified several biomarkers in tumor tissues 
whose levels either increase or decrease upon exposure to BBI608.  Tumor biopsies will be collected 
as described below.  The goal of the proposed biomarker study is to examine the response of 
biomarkers in patients treated with BBI608. Subject tumor samples will be processed for 
determination of pharmacodynamic markers in malignant tissue by histopathology and CSC assays. 
 
6.6 Tumor Biopsy  
Patients who are identified by the Principal Investigator as having an easily accessible lesion, which 
could be biopsied with a minimally invasive procedure, will be asked to sign an additional consent.  
Patients with easily accessible tumors who consent to the optional biopsy should have a baseline 
biopsy prior to starting treatment with BBI608, and an on-treatment tumor biopsy which will be 
collected on Day 1 of Cycle 2 (+/- 2 days) of the first cycle of treatment with BBI608.   
 
An easily accessible lesion is a lesion which, in the opinion of the Study Investigators, could be 
biopsied with a minimally invasive procedure, and with minimal risk to the patient.  The baseline 
biopsy, if applicable, needs to be obtained no more than 1-week prior to the first dose of BBI608.   
 
The on-treatment biopsy will be collected approximately 4-6 h after the first administration of 
BBI608 on Day 1 of Cycle 2.  (If a patient withdraws from the study, or if a DLT occurs and the 
patient stops taking BBI608 prior to Day 1 of Cycle 2, then the on-treatment biopsy will be canceled.)    
 
In addition, archival tissue samples from a previous resection or biopsy should be collected from all 
patients enrolled in the clinical trial if they are available. 
 


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June 23rd, 2017 
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Amendment #4 
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Collection, storage, and shipping of tissue samples will be performed as described in Appendix G: 
Tumor Biopsies.  Tumor samples may be used for the following investigations: 
• 
Pharmacodynamics 
• 
Pharmacokinetics (see section 6.4 and Appendix F) 
 
Other investigations on tumor samples may be performed as determined by the study investigators 
and/or study sponsors.  If the patient grants permission, tumor samples may be stored for additional 
future studies.   
 
7 TREATMENT 
7.1 BBI608 
BBI608 capsules or tablets will be supplied to the pharmacy at the clinical sites.  Study drug will be 
labeled as an investigational agent, limited by federal law.  The pharmacist will dispense an 
appropriate number of each strength capsule or tablets to the Principal Investigator for in-clinic 
dosing.  The appropriate quantity of capsules or tablets will be dispensed to the patient for each cycle 
(see Section 5.4 and Appendices A, B, C and D).  
BBI608 is supplied in 80 mg capsules or tablets and should be stored at room temperature (15-25 
degrees Celsius).  These instructions must appear on the label for the container in which capsules or 
tablets are delivered to the patient.   
 
7.1.1 
Investigational Product Accountability 
BBI will provide all study drug required for completion of this study.  The recipient will acknowledge 
receipt of the drug indicating shipment content and condition.  Damaged supplies will be replaced.  
Until dispensed to the patients, the 80 mg capsules or tablets will be stored in a temperature 
controlled, secure locked area, accessible to authorized personnel only, at room temperature (15-25 
degrees Celsius). 
Accurate records of all study drug dispensed from and returned to the study site are to be maintained.  
The study site must supply a copy of their drug destruction policy to BBI before authorization for 
destruction will be granted.  Product accountability will be monitored throughout the study.  Upon 
completion or termination of the study, and after inventory by a BBI monitor or designated 
representative, all unopened drug is to be returned to BBI, or designee, in the original containers.  
 
7.1.2 
BBI608 Administration 
BBI608 will be administered continuously by mouth twice daily, with doses approximately 12 hours 
apart for 28 consecutive days.  BBI608 should be administered approximately one hour prior to or 
two hours after meals, with the first dose given in the morning.   
The dose of BBI608 to be administered depends on the dose level cohort to which the patient is 
enrolled.  See Section 4.1 for details. 
Intra-patient dose escalation is permitted if the new dose level cohort is complete and proven safe.  
Intra-patient dose escalation can occur following the agreement of both the Principal Investigator and 
the medical monitor of the Sponsor. 


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June 23rd, 2017 
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Intra-patient dose de-escalation is allowed due to adverse events, pharmacokinetic data, or pill 
burden, provided that the new dose level is below MTD (maximum tolerated dose) and the new dose 
level is agreed upon by the Principal Investigator and the medical monitor of the Sponsor. 
 
7.1.3 
FOLFOX6 with and without Bevacizumab, CAPOX, FOLFIRI with and 
without Bevacizumab, Regorafenib or Irinotecan Administration 
Detailed instructions for the preparation, premedication, and administration of FOLFOX6 with and 
without bevacizumab, CAPOX, FOLFIRI with and without bevacizumab, regorafenib or irinotecan 
are provided in the Product Labels approved by Health Canada or US FDA. 
ARM A- FOLFOX6 – Oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 will be 
administered intravenously starting on Day1 of Cycle 1, after the first daily dose of BBI608**. 5-FU 
400 mg/m2 bolus will be administered intravenously immediately following oxaliplatin/leucovorin 
infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) continuous 
intravenous infusion This regimen will be repeated every 14 days thereafter. In case of toxicity, dose 
adjustment is permitted. 
ARM B- FOLFOX6 plus bevacizumab - Oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 
will be administered intravenously over 2 hours starting on Day1 of Cycle 1, following the first daily 
dose of BBI608*. 5-FU 400 mg/m2 bolus will be administered intravenously immediately following 
oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 
hours) continuous intravenous infusion.  Bevacizumab 5 mg/kg will be administered intravenously 
following oxaliplatin/leucovorin infusion. This regimen will be repeated every 14 days thereafter. In 
case of toxicity, dose adjustment is permitted. 
ARM C- A CAPOX regimen will be administered orally (capecitabine) and IV (oxaliplatin). Starting 
on Day 1 of Cycle 1, capecitabine 850 mg/m2 will be administered orally twice-daily following the 
first daily dose of BBI608* for 14 consecutive days and be repeated every 21 days. Oxaliplatin 130 
mg/m2 will be administered IV over 2 hours, following the first daily dose of BBI608* starting on 
Day 1 of Cycle 1 and be repeated every 21 days thereafter. In case of toxicity, dose adjustment is 
permitted. If capecitabine is tolerated at the 850 mg/m2 twice daily dose, dosage may be increased to 
1000 mg/m2 twice daily as tolerated after the first cycle. 
ARM D- A FOLFIRI** – Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 will be 
administered intravenously starting on Day 1 of Cycle 1, following the first dose of BBI608*. 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 every 14 days thereafter. In case of toxicity, dose adjustment is permitted. 
ARM E- FOLFIRI plus bevacizumab - Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 
will be administered intravenously starting on Day 1 of Cycle 1, following the first dose of BBI608*. 
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. Bevacizumab 5 mg/kg will be administered intravenously following oxaliplatin/leucovorin 
infusion. This regimen will be repeated every 14 days thereafter. In case of toxicity, dose adjustment 
is permitted. 
ARM F- Regorafenib 120 mg will be administered orally once daily, with a low-fat meal, starting on 
Day 1 of Cycle 1, following the first daily dose of BBI608* and be continued for 21 consecutive days 
of every 28 days thereafter. In case of toxicity, dose adjustment is permitted. If regorafenib is 
tolerated in the first cycle, dosage may be increased to 160 mg once daily as tolerated after the first 
cycle. 


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ARM G- Irinotecan 180 mg/m2 will be administered intravenously starting on Day 1 of Cycle 1, 
following the first dose of BBI608. This regimen will be repeated every 14 days thereafter. In case of 
toxicity, dose adjustment is permitted. 
 
*A 3 hour interval between the first daily dose of BBI608 and the initiation of combination therapy is 
required on PK days during Cycle 1 only, in order to standardize PK interpretation. On all other days, 
the first daily administration of BBI608 should precede the administration of combination therapy by 
1-4 hours. 
** FOLFIRI/XELIRI-refractory patients enrolled as part of the 50 evaluable patient expansion cohort 
can resume FOLFIRI at the last dose that they received prior to progression on their prior FOLFIRI 
treatment. 
 
7.2 Dose Modifications 
7.2.1 
BBI608 
For any BBI608-related intolerable grade 3 or intolerable grade 2 adverse events, persisting despite 
optimized medical management, a dose holiday of 1-3 days followed by dose modification is 
recommended. The dose can be reduced by 1/3 or ½ (as allowed by capsule or tablet strength). For 
instance, if a patient requires a dose modification at the dose level of 240 mg twice daily, the dose can 
be reduced to 160 mg twice daily. If a patient requires a dose modification at the dose level of 480 mg 
twice daily, the dose can be reduced to 240 mg twice daily. Investigators should discuss dose 
modifications with the medical monitor for the sponsor. Patients should up-titrate dose with the goal 
of achieving full dose as tolerated.  
If a toxicity is thought by the Investigator to be related to both BBI608 and the combination regimen 
(FOLFOX6 with and without bevacizumab, CAPOX, FOLFIRI with and without bevacizumab, 
regorafenib or irinotecan), then the dose modification rules for both BBI608 and the combination 
regimen should be followed.  
 
7.2.2 
FOLFOX6 with and without Bevacizumab, CAPOX, FOLFIRI with and 
without Bevacizumab, Regorafenib and Irinotecan 
Dose modifications for toxicities expected from combination agents/regimen should be performed 
according to the Investigator, as per Product Labels approved by Health Canada or US FDA, 
respectively.  
 
7.3 Treatment Compliance 
A patient is considered compliant with the study protocol when study medication is administered at a 
compliance level of greater than 80%.   
BBI608 compliance will be calculated using the following equation: 
(Number of capsules or tablets actually ingested /number of capsules or tablets that should have been 
ingested per dose level) x 100 = % compliance 
For any IV combination drug, compliance will be calculated using the following equation: 
(Number of treatments administered /number of treatments that should have been administered) x 
100= % compliance 


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For any oral combination drug, compliance will be calculated using the following equation: 
(Number of capsules actually ingested /number of capsules that should have been ingested) x 100 = % 
compliance 
 
7.4 Blinding 
This is an open label study.  Neither the patient nor the investigator and site staff will be blinded to 
the treatment administered. 
 
7.5 Prior Treatment 
Reasonable efforts will be made to determine all relevant prior treatments received by the patient 
within four weeks of the first BBI608 dose. All relevant information must be recorded on the 
appropriate patient's Case Report Form (CRF).  All surgical procedure history, prior chemotherapy 
and radiation therapy must be recorded on the appropriate CRF. 
 
7.6 Concomitant Medication 
7.6.1 
Permitted Treatment 
All information regarding concomitant treatments (medications or procedures) must be recorded on 
the patient’s CRF (including the name of the medication or procedure and duration of treatment).  
Palliative and supportive care for disease-related symptoms will be offered to all patients in this 
study.   
BBI608 was shown in vitro to inhibit individual CYP P450 isoforms 1A2, 2D6, 2C19, 3A4, and 2C9 
with IC50’s of 0.25 µM, 0.25 µM, 2.5 µM, 5 µM, and 0.5 µM respectively, under serum-free 
conditions. Since in vitro, BBI608 has shown the ability to inhibit these CYP P450 isoforms, 
concomitant use of agents that are substrates of these CYP P450 enzymes should be avoided unless 
deemed medically necessary by the  primary investigator. Examples of commonly prescribed agents 
that are metabolized by these CYP P450 enzymes are: 
 NSAIDS: such as ibuprofen, naproxen 
Proton pump inhibitors: such as lansoprazole, omeprazole  
Oral hypoglycemic medications: sulfonylureas  
Beta-blockers: metoprolol, carvedilol  
Calcium channel blockers: amlodipine, diltiazem, nefedipine, verapamil  
Antidepressants: paroxetine, imipramine, amitriptyline  
Anti-epileptics: such as phenytoin, phenobarbitone  
Anti-psychotics: such as haloperidol, risperidone  
Antibiotics: such as clarithromycin, erythromycin  
HMG CoA reductase inhibitor: atorvastatin, lovastatin, simvastatin  
Anesthetics: such as halothane, enflurane; 
HIV antivirals: such as saquinavir, indinavir, ritonavir  
Immunomodulators (immunosuppressives): such as cyclosporine, tacrolimus 
Steroids: such as hydrocortisone, estrodiol 
 
BBI608 is metabolized by the CYP P450 isoform 1A2. Therefore, concomitant use of drugs which 


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inhibit CYP1A2 should be avoided unless deemed medically necessary by the primary investigator. 
Known drugs that inhibit CYP 1A2 include ciprofloxacin and other fluoroquinolones, Fluvoxamine 
Verapamil, amiodarone, interferon, methoxsalen, enoxacin, mexiletine, and ticlopidine. 
Of note, no clinically apparent drug-drug interactions occurred during phase 1, phase 1b/2 studies 
conducted on BBI608 thus far. 
In addition, the following treatments are allowed: 
• 
Standard therapies for concurrent medical conditions 
• 
Epoetin alfa (Epogen®, Procrit®)  
• 
Hematopoietic growth factors, including filgrastim (Neupogen®), or other granulocyte colony 
stimulating factors (G-CSF), are permitted following documented and clinically significant 
neutropenia after the patient has completed at least one cycle of treatment with BBI608 
• 
Prophylactic antiemetics may be administered according to standard practice  
• 
Low dose corticosteroids used as an antiemetic regimen 
• 
Megestrol acetate (Megace®)  
 
7.6.2 
Prohibited Treatment 
• 
Any concurrent chemotherapy, radiotherapy, (palliative radiotherapy for non-target lesions 
may be permitted in certain cases as decided by the principal investigator and sponsor), 
hormonal therapy, or immunotherapy 
• 
Other investigational agents 
Immunosuppressive therapies, including systemic corticosteroids such as prednisone 
10 mg daily or equivalent (except when used intermittently in an antiemetic regimen)  
 
8 SAFETY ASSESSMENTS 
8.1 Adverse Events  
8.1.1 
Assessments 
The Investigator is responsible for monitoring the safety of patients who have enrolled in the study.  
All AEs considered to be related to BBI608 occurring after any administration of the study drug will 
be followed until the event resolves.  AEs will be evaluated using the National Cancer Institute (NCI) 
CTCAE, Version 4.0.  
Investigators are required to document all AEs occurring during the clinical trial, commencing with 
the first dose of BBI608 and including the protocol-defined post-treatment follow-up period (21 Code 
of Federal Regulations [CFR] §312.64[b]) on designated CRF pages.  AEs occurring following the 
signature of the informed consent, but prior to the first dose of study drug will not be reported as AEs.  
It is also important to record all AEs that result in permanent discontinuation of the investigational 
product being studied, whether serious or non-serious. 
Serious adverse events (SAEs), as defined below, must be reported to Boston Biomedical Inc. or its 
representative within 24 hours of knowledge of their occurrence. 
8.1.2 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical investigational patient 
administered a pharmaceutical product that does not necessarily have to have a causal relationship 
with the treatment.  An AE can, therefore, be any unfavorable and unintended sign (including an 


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abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of 
a medicinal product, whether or not considered related to the medicinal product. 
Laboratory data are to be collected as stipulated in this protocol, and toxicity trends will be analyzed 
utilizing objective toxicity criteria.  Clinical syndromes associated with laboratory abnormalities are 
to be recorded as appropriate (e.g., diabetes mellitus instead of hyperglycemia).   
Progression of disease is considered an efficacy outcome parameter and should not be captured as an 
AE.  A non-serious AE is any untoward medical occurrence that does not meet any of the criteria for 
SAEs as defined below. 
Patients should be instructed to report any AE that they experience to the Investigator.  Investigators 
should assess the patient for AEs at each visit.  AEs occurring during the clinical trial and the follow-
up period should be recorded on the appropriate AE CRF.  To capture the most potentially relevant 
safety information during a clinical trial, it is important that investigators record accurate AE terms on 
CRFs. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the CRF.  However, if an observed 
or reported sign or symptom is not considered a component of a specific disease or syndrome by the 
investigator, it should be recorded as a separate AE on the CRF. 
 
8.2 Serious Adverse Events 
8.2.1 
Definitions 
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any of 
the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization   
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
Important medical events may be considered an SAE based upon appropriate medical judgment.   
Under this protocol, scheduled hospitalizations or elective surgical/medical procedures or elective 
hospitalization will not be considered SAEs.  Prolongation of a scheduled hospitalization can be 
considered an SAE.  Complications associated with scheduled procedures are considered an AE. 
8.2.2 
Reporting Serious Adverse Events 
Any SAE, including death, due to any cause that occurs during this investigation, whether or not 
related to the administration of study drug, must be reported to the Sponsor immediately (not to 
exceed 24 hours) by telephone, secured email or facsimile.  The reaction must be completely 
described on the CRF and SAE report form. 


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9 ASSESSMENT OF ANTI-TUMOR ACTIVITY 
The following definitions and criteria (from Response Evaluation Criteria in Solid Tumors [RECIST 
1.1, Eisenhauer et al., 2009]) should be used for the baseline evaluations of existing disease, and for 
the ongoing evaluation of tumor responses. 
Measurable disease - presence of at least one measurable lesion.  
Measurable lesions - lesions that can be accurately measured in at least one dimension with longest 
diameter ≥10 mm using conventional techniques or ≥10 mm with spiral CT scan.  Malignant lymph 
nodes must be >15 mm in the shortest diameter. 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <10 mm with 
conventional techniques or <10 mm with spiral CT scan or >10 mm to <15 mm in short axis), i.e., 
bone lesions, ascites, pleural/pericardial effusion, cystic lesions and also abdominal masses that are 
not confirmed and followed by imaging techniques. 
• 
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. 
• 
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. 
• 
Lesions identified by clinical exam will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  For the case of skin 
lesions, documentation by color photography, and a measurement with a ruler to 
estimate the size of the lesion, is recommended. 
 
9.1 Central Radiology Review 
A central radiology review will be used for this study. A central imaging reviewer will provide an 
independent review of response and progression only for the FOLFIRI/XELIRI-refractory CRC 
patients enrolled onto the study on the FOLFIRI (with bevacizumab if clinically indicated) 
combination arm. Collection of all on-study CT/MRI scans for all FOLFIRI/XELIRI-refractory CRC 
patients enrolled on the study will be included as part of the review. 
 
Films or electronic copies should be collected by the investigative sites and sent to the central image 
reader. Complete details regarding image handling and submission can be found in the Radiology 
Technical Manual. 
Primary Medical Monitor Contact information: 
Laura Borodyansky, MD 
Boston Biomedical, Inc 
640 Memorial Drive 
Cambridge, MA 02139 
Telephone: (617) 674-6800 ext 8705 
Fax: (617) 674-6800 
Email: lborodyansky@bostonbiomedical.com 
Emergency Number:  339-364-5611 


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9.2 Methods of Measurement 
• 
CT and MRI are the best currently available and reproducible methods to measure 
target lesions selected for response assessment.  Conventional CT and MRI should be 
performed with cuts of 10 mm or less in slice thickness contiguously.  Spiral CT 
should be performed using a 5 mm contiguous reconstruction algorithm. 
• 
All imaging methods should be performed according to institutional standards with 
each patient having consistency of methods beginning from baseline through the 
course of the study. 
 
9.3 Baseline Documentation of “Target” and “Non-Target” Lesions 
• 
All measurable lesions up to a maximum of five lesions total with a maximum of 2 
lesions per organ, representative of all involved organs should be identified as target 
lesions and recorded and measured at baseline. 
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinical assessments). 
• 
A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD.  The baseline sum LD will be used as the reference 
by which to characterize the objective tumor response.  
• 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up. 
 


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9.4 Response Criteria 
 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short 
axis of <10mm 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started. In addition to the increase of 
20%, the sum must also demonstrate an absolute increase of 
at least 5mm.  The appearance of one or more new lesions is 
also considered progression. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-
pathological in size (<10mm short axis) 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions  
 
9.5 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence and is determined as indicated in the table below: 
 
 
 
Target 
lesions 
Non-Target lesions 
Evaluation of New 
lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
10 PLANNED STATISTICAL METHODS 
10.1 General Considerations 


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Phase Ib: 
Because of the nature of this study, no formal statistical analysis is planned.  Evaluation of the data 
will consist primarily of summary displays (i.e., descriptive statistics and graphs).   
Phase II: 
Efficacy in the FOLFIRI/XELIRI-refractory expansion cohort will be evaluated as a single stage 
design. 
 
10.2 Determination of Sample Size 
Phase Ib: 
The sample size for this study was determined by clinical rather than statistical considerations.  With 
cohort sizes of three to six patients, if the true underlying rates of DLT are 0.1, 0.2, 0.3, 0.4, and 0.5, 
there will be 91%, 71%, 49%, 31%, and 17% chances, respectively, of escalating to the next full dose. 
Phase II: 
Anti-tumor activity of the FOLFIRI/XELIRI-refractory CRC patients enrolled will be evaluated as a 
single stage design. Evaluable patients will include all FOLFIRI/XELIRI-refractory CRC patients 
who receive on-study tumor response assessment. This analysis will test the following: 
Ho: π ≤ 0.05 
Versus 
Ha: π > 0.05 
If ORR response rate with FOLFIRI treatment alone is estimated at 5% and a true ORR response rate 
with FOLFIRI (with bevacizumab if clinically indicated) in combination with BBI608 is 12%, a 
sample size of 50 evaluable patients produces a two-sided 95% confidence interval with a width of 
0.2, for a 95% exact confidence interval of 4.5%-24.5%.  
 
10.3 Analysis Populations 
All patients receiving at least one dose of BBI608 will be considered evaluable for safety analysis.  
Adverse event incidence rates will be described by the frequency of adverse events, categorized by 
NCI CTCAE version 4.0.  Listings of laboratory test results collected at baseline and during the study 
will be generated.  Descriptive statistics summarizing the changes in those laboratory tests over time 
will be presented.  
Patients evaluable for dose escalation are defined as having been exposed to at least 28 days of 
continuous daily administration of BBI608, starting from Cycle 1 Day 1. 
Patients who have received at least one cycle of study treatment and have had at least one disease 
assessment following the initiation of therapy will be considered evaluable for response.  Anti-tumor 
activity will be evaluated on an exploratory basis and will be summarized using descriptive statistics 
or graphics. 
 
10.4 Demographics and Baseline Characteristics 
Patient characteristics will include a summary of the following: 
• 
Patient demographics 
• 
Baseline disease characteristics 


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• 
Pre-existing conditions 
• 
Prior therapies 
• 
Concomitant medications and treatments 
Other patient characteristics will be summarized as appropriate 
 
10.5 Statistical Analysis of Pharmacokinetic Variables 
Timed blood sample collection for pharmacokinetic analysis will be performed on Days 1 (for all 
patients), 15 (for FOLFOX6 with and without bevacizumab and FOLFIRI with and without 
bevacizumab and regorafenib arms ONLY), and 22 (for CAPOX arm ONLY) during Cycle 1. 
Timed blood sample collection for pharmacokinetic analysis will additionally be performed for 
patients who experience a dosing regimen modification.   
These sample collections will be according to the parameters outlined in Sections 6.4, 6.5, and 
Appendices A, B, C and D. 
Bioanalytical analysis of patient samples will be conducted at a centralized laboratory using GLP-
validated assays.  Plasma concentrations will be summarized by descriptive statistics, including mean, 
standard deviation, coefficient of variation, minimum, maximum, and median.   
Concentration profiles will be analyzed by non-compartmental and/or non-linear least squares 
regression using WinNonLin.  Pharmacokinetic parameters, including Cmax, volume of distribution, 
distribution half-life, terminal half-life, and AUC will be evaluated.  
 
10.6 Safety Analysis 
Safety will be assessed by physical examination, and laboratory assessments.  Adverse events will be 
graded according to the NCI CTCAE, version 4.0.  The incidence of adverse events and DLTs will be 
evaluated for each dose level, and for all patients combined.  Patients will be followed for adverse 
events for at least 30 days after the last dose of BBI608, or until recovered from all related BBI608 
adverse events.  
 
11 QUALITY CONTROL AND ASSURANCE 
The study will be initiated and conducted under the sponsorship of Boston Biomedical.  Study drug, 
clinical supplies, and CRFs will be supplied by Boston Biomedical, or its representative.  
Representatives of Boston Biomedical will monitor the study to verify study data, medical records, 
and CRFs in accordance with current ICH GCPs and other applicable regulations and guidelines. 
 
11.1 Compliance with the Protocol 
The Investigator will notify the Sponsor of any deviations from the protocol.  Such contact with the 
Sponsor will be made as soon as possible to permit a decision as to whether or not the subject (for 
whom the deviation from the protocol was effected) is to continue in the study.  The case records will 
describe the deviation from the protocol and state the grounds for it. 
 


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11.2 Registration and Enrollment 
This is an open-label, non-randomized study.  Boston Biomedical should be notified as soon as a 
subject qualifies for entry in the protocol.  Subjects will be registered by faxing Boston Biomedical or 
their designee, within 7 (+2) days prior to the 1st drug administration.  At that time the dose level will 
be assigned.  The subject will be enrolled into the study when the subject receives the 1st dose of 
study drug.  Registration and enrollment forms and faxing instructions will be provided with the Case 
Report Forms (CRFs).  The site should maintain a log of all subjects who are screened (i.e., who sign 
consent) but do not qualify for the study, or who do not receive study drug.  The reason for 
disqualification should be noted in the log. 
 
11.3 Removal, Replacement, or Early Withdrawals of Subjects 
If a subject exits the study prior to receiving four weeks of study drug or does not receive four weeks 
of study drug for a reason other than DLT, an additional subject may be recruited to replace the 
subject. 
  
12 COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL 
 
CONSIDERATIONS AND INFORMED CONSENT 
12.1  Institutional Review Board 
 
 
The protocol, any protocol modifications, informed consent form that will be used, and, if 
applicable, the permission to use private health information must be approved by the 
Investigator’s IRB or Independent Ethics committee (IEC) before the study is initiated.  
Documentation of this approval (i.e., a copy of the document showing IRB/IEC approval 
including the chairperson’s signature and the date of approval) must be provided to Boston 
Biomedical or its designee, and made available during an inspection by the FDA or other 
regulatory agency inspectors.  The Investigator will submit to Boston Biomedical: 
 
- 
A list of the names, occupations, and affiliations of the members of the IRB 
- 
Documentation that the IRB is duly constituted or a General Assurance Number 
- 
No supplies will be shipped until the IRB has given written approval of the protocol 
and informed consent and Boston Biomedical has received copies of the approvals 
 
It is the responsibility of the Investigator to: 
 
- 
Submit to the IRB/IEC for review any advertisements that will be used to recruit 
subjects 
- 
During the conduct of the study, submit progress reports to the IRB, if required, and 
request review of the study  
- 
Report, in writing, to the IRB all SAEs that occurred during the study or SAEs 
reported in other studies using study drug, per local IRB regulations 
- 
Inform the IRB of any changes in the protocol and obtain documented IRB approval 
of the changes 
- 
Maintain a file of study-related information, including all correspondence with the 
IRB/IEC 
- 
Within 3 months of study completion, provide the IRB with a final report on the 
study 
 


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12.2  Compliance with Good Clinical Practice and Ethical Considerations 
 
This study must be conducted in compliance with IRB/IEC informed consent regulation and 
the ICH GCP Guidelines.  In addition, all local regulatory requirements will be adhered to, in 
particular those which afford greater protection to the safety of the trial participants. 
 
This study will be conducted according to the current revision of the Declaration of Helsinki 
(Revised Edinburgh, Scotland, 2000) and with local laws and regulations relevant to the use 
of new therapeutic agents in the country of conduct. 
 
Before initiating a trial, the Investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the trial protocol/amendment(s), written 
informed consent form, patient recruitment procedures (e.g., advertisements) and written 
information to be provided to patients. 
Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) 
to patients. 
 
12.3 
Informed Consent and Permission to Use Private Health Information 
The Investigator, or designee, is responsible for the content of the informed consent form, but 
the content must be submitted and approved by Boston Biomedical, prior to submission to the 
IRB.  Before the start of required study procedures, the Principal Investigator or associate 
must obtain informed consent from each study participant (or the subject’s parent/guardian) 
in accordance with ICH document “Guidance for Industry – E6 Good Clinical Practice: 
Consolidated Guidance” dated April 1996.  It should also include any additional information 
required by local laws relating to institutional review. 
 
Informed consent must be obtained from the subject before any screening activity, washout of 
medication, or treatment (that is not part of routine care) is undertaken.  Informed consent 
will be obtained by discussing with the subject the purpose of the study, the risks and 
benefits, the study procedures, and any other information relevant to the subjects. 
 
The subject or his/her legal representative will document their informed consent by signing 
the current version of the written, IRB-approved, informed consent form in the presence of a 
witness. 
 
The person, who conducted the informed consent discussion with the subject and/or guardian, 
must also sign the informed consent form.  The subject should be given a copy of the 
informed consent form with all of the appropriate signatures. 
 
The Principal Investigator will ensure that a copy of the signed consent is kept with the 
Clinical Trial Master File. 
 
The Investigator or designee must explain to the patient subject that for evaluation of study 
results, that subject’s private health information obtained during the study may be shared with 
the study Sponsor, regulatory agencies, and ECs/IRBs, before enrolling that subject into the 
study. It is the Investigator’s (or designee’s) responsibility to obtain permission to use private 
health information from each subject, or if appropriate, the subject’s legal guardian. 


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13  STUDY MANAGEMENT 
13.1  Amendments to the Protocol 
Once the protocol has been approved by the IRB, the Investigator will not modify it without 
obtaining the prior concurrence of Boston Biomedical.  In turn, Boston Biomedical will 
inform the Investigator in writing of any amendment to the protocol.  The Investigator must 
submit the protocol modifications and any informed consent modifications to the IRB, and 
approval must be obtained before the modifications are implemented.  Boston Biomedical 
will submit protocol modifications to Health Canada. 
 
13.2  Investigator Brochure and Information Materials 
Before the study begins, the Investigator will receive an Investigator’s Brochure describing 
all known contraindications, warnings, precautions, and adverse reactions associated with the 
administration of the study drug.  If such information is revised while the study is in progress, 
the brochure will be amended or revised, and Boston Biomedical will provide the most 
current version to the Investigator. 
 
13.3  Pre-investigational Documents 
Prior to the shipment of the study drug(s), the Investigator will supply Boston Biomedical 
with the following: 
 
- 
A signed Investigator Clinical Research Agreement 
- 
A completed Form FDA 1572 signed by the Investigator 
- 
Current curricula vitae and copy of current medical license for the Principal 
Investigator and Sub-Investigators listed on Form FDA 1572 
- 
A completed financial disclosure form for all personnel listed on Form FDA 1572 
- 
Signed and dated protocol signature page by the Principal Investigator 
- 
A copy of the approval for this protocol from the IRB listed on Form FDA 1572 
- 
A copy of the approval for the informed consent from the IRB listed on Form FDA 
1572 
- 
A copy of the IRB-approved informed consent 
- 
Evidence of laboratory certification and a list of laboratory normal ranges for all 
laboratories listed on Form FDA 1572 
- 
A list of the IRB members (for the IRB on Form FDA 1572) and the member 
occupations and affiliations; written verification that the IRB is duly constituted or 
the General Assurance Number 
 
13.4  Drug Inventory Record 
The Investigator, or a responsible party (research pharmacist or other) designated by the 
Investigator, must maintain an inventory record of drug received and dispensed.  Boston 
Biomedical will provide forms to facilitate the inventory control.  These forms must be used 
unless the Investigator has previously established a system that complies with FDA and/or 
Health Canada regulations and is approved by Boston Biomedical.  The study drug must be 
dispensed only to the institution(s) specified on form FDA 1572. 
 


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13.5  Disposition of Used and Unused Study Drug 
Upon completion or termination of the study and after inventory by a Boston Biomedical 
monitor or designated representative, all unopened drugs are to be returned to Boston 
Biomedical in the original containers.  All used vials will be retained until released for 
destruction by the Boston Biomedical monitor. Unopened returned drugs, with completed 
Boston Biomedical forms for return shipment, should be shipped as instructed by the 
Sponsor. 
 
13.6  Study Records 
Boston Biomedical will provide the Investigator with drug shipment records, CRFs designed 
to collect the data specified for each individual, and other forms as necessary. 
 
The Investigator and/or institution is required to prepare and maintain these forms in 
accordance with federal regulations (set forth in the Statement of Investigator Form FDA 
1572) and to sign, date, and return them to the Sponsor. 
 
Upon the request of authorized Boston Biomedical or appropriate regulatory agency 
personnel, the Investigator will make available for inspection subject source documents, e.g., 
records of each subject who participates in this study.  This information will be treated as 
confidential. 
 
13.7  Record Retention 
Records must be maintained for 25 years: 
 
If the Investigator leaves the institution where the study was conducted, he/she agrees that the 
records will be retained and will not be destroyed without prior notification of Boston 
Biomedical. 
 
Boston Biomedical will notify the Investigator when records are no longer required. 
 
13.8  Subject Confidentiality 
Every effort will be made to keep all subject identities confidential.  All reports and 
communications submitted to the Sponsor will be identified only by the subject’s initials and 
subject number.  The identity of an individual subject may not be disclosed in any publication 
relating to this study. 
 
In connection with this study, representatives of the Health Canada, or other regulatory 
bodies outside of Canada, such as the United States Food and Drug Administration, and 
representatives of the local IRB may, in certain circumstances, review study source 
documentation including subject medical records. 
 
13.9  Monitoring 
In accordance with good clinical practices, the study will be monitored by Sponsor 
representatives.  These representatives will have access to and will review source documents 
relating to this study, including subject medical records. 
 
The status of drug storage, dispensing, and accountability will also be assessed during 
periodic visits. 


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At any time, each site may be audited either by Boston Biomedical personnel, or by a 
contractor acting on behalf of Boston Biomedical, or by a regulatory agency such as the FDA 
or Health Canada. 
 
13.10 Case Report Form (CRF) Completion 
A set of CRFs will be provided for each study subject.  All forms must be filled out in non-
erasable ink or typed.  The Investigator will sign and date each CRF as indicated.  Correction 
of data on a CRF will be made by crossing out the incorrect data in a manner that leaves the 
previous entry legible and writing the correct information next to the crossed out entry.  
“White-out” and erasures are not permitted.  Each correction must be initialed and dated by 
the individual making the correction.  After the CRFs have been collected by Boston 
Biomedical, all corrections will be made via a query resolution form, and no further 
corrections should be made on the site’s copy of the CRF. 
 
13.11 Final Site Report 
The Principal Investigator or associate must notify the IRB when the study is closed and 
provide a final report to the IRB within 90 days of the last subject’s completion of the study.  
A copy of this final report must also be provided to Boston Biomedical. 
 
13.12 Final Study Report 
At the conclusion of the study, after the data are analyzed, Boston Biomedical will prepare a 
final study report.  A copy of this report will be provided to the Principal Investigator at each 
center. 
 
The preparation of the final study report may be delegated to a contract research organization. 
 
13.13 Use of Information 
All personal information pertaining to subjects in this study and in any subsequent reports 
will be kept confidential.  Subjects will be identified only by their initials and by a subject 
number.  It is the responsibility of the Investigator to keep a subject listing for cross-
referencing. 
 
The Investigator understands that the information developed in the clinical study will be used 
by Boston Biomedical in connection with the development of the study drug.  This 
information may be disclosed to other clinical investigators, the FDA, Health Canada, and 
other government agencies. 
 
All information disclosed to the Investigator(s) by Boston Biomedical for the purpose of 
having the Investigator(s) conduct the clinical trial described in this protocol or generated by 
the Investigator(s) as results in the clinical trial shall be treated by the Investigator(s) as 
strictly confidential.  The Investigator(s) shall not use such information other than for the 
purpose of conducting the clinical trial and may not disclose such information to others, 
except when such disclosure is to colleagues and/or employees who reasonably require the 
information to assist in carrying out the clinical trial and who are bound by like obligations of 
confidentiality.  Notwithstanding, the Investigator(s) may use or disclose to others any 
information which: (i) was known to the Investigator(s) prior to the date of its disclosure, (ii) 
is now, or becomes in the future, publicly available; or (iii) is lawfully disclosed to the 


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June 23rd, 2017 
BBI608-246 
 
Amendment #4 
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Page 60 
Investigator(s) on a non-confidential basis by a third party who is not obligated to Boston 
Biomedical or any other party to retain such information in confidence. 
 
13.14  Publication 
Boston Biomedical acknowledges that the Investigator(s) have certain professional 
responsibilities to report to the scientific community on findings in clinical investigations 
they conduct.  The Principal Investigator shall have the right to publish the results of research 
performed under this protocol, provided such publication does not disclose any Confidential 
Information or trade secrets of Boston Biomedical (other than the Clinical Data).  If the Study 
is conducted as part of a multi-center protocol, Principal Investigator agrees not to 
independently publish their findings except as part of an overall multi-center publication, 
unless specifically approved in writing by Boston Biomedical.  The Principal Investigator 
agrees to, prior to submitting a manuscript, abstract, or any other written or oral presentation 
describing the Data for publication or presentation, forward to Boston Biomedical a copy of 
the item to be submitted for publication or presentation.  Upon reasonable request by Boston 
Biomedical within 30 days of receipt, the Principal Investigator agrees to withhold such 
publication an additional 60 days to permit the preparation and filing of related patent 
applications.  In addition, Boston Biomedical shall have the right to require the Principal 
Investigator to delete from any publication or presentation any Confidential Information 
(other than the Clinical Data) of Boston Biomedical’s and to require that any publication or 
presentation concerning the Study acknowledge the Sponsor’s support. 
 
13.15 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. 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
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Page 61 
APPENDIX A:  SCHEDULE OF ASSESSMENTS FOR FOLFOX6 WITH OR WITHOUT BEVACIZUMAB (ARMS A AND B) 
Tests & Procedures
Pre-Study 
Evaluation
End of Study Visit
Week
0
1
3
3
Day
up to 9 days 
before 1st dose 
of BBI608 
[-]5
1
15
15
At least 30 days from 
last BBI608 dose
Written informed consent1
X
Medical history
X
Physical examination
X
X
Serum pregnancy test
X
Karnofsky performance status score
X
X
X
X
X
X
Vital signs, Weight
X
X
X
X
X
X
Hematology2
X
X
X
X
X
Biochemistry2
X
X
X
X
Urinalysis2
X
X
X
X
12-Lead electrocardiogram
X
X
X
Tumor markers (if applicable)2
X
X
Tumor biopsy (if applicable)3
X
Pharmacokinetics
X
X
Tumor measurement & staging4,5,6
X7
X
Concomitant medications
X
X
X
X
X
X
Adverse events8
X
X
X
X
FOLFOX6  ± Bevacizumab9
X
X
X
Dispense BBI60810
X
X
X
X
X
X
X
X
X
X
X
X
X
Additional Cycles
On Study Evaluations (+/- 2 days)
X
1
1
Cycle 1
 
1. 
Written informed consent may be obtained up to 1 month prior to first dose of BBI608     
2. 
Refer to Section 6.3 for description of laboratory assessments. 
3. 
Archival Tissue samples will be obtained per Appendix G once the patient has been enrolled. 
4. 
Including tumor measurements, following RECIST 1.1.  
5. 
At the end of cycle 2 and every other cycle thereafter, assessments must be made utilizing the same imaging method as baseline 
6. 
If at any time during the tumor evaluation visits either a partial or complete response is observed, the same radiographic study should be repeated within four weeks for confirmation of response. 
7. 
 Unless CT/MRI has been performed within last three weeks. 
8. 
Patients will be followed until resolution of any drug-related AE or SAE occurring during the study or within 30 days of last BBI608 administration. 
9. 
FOLFOX6 with or without bevacizumab will be administered as per standard schedule. 
10. BBI608 will be dispensed in a 5-day plus 2 extra day supply on day [-]5, 28 day supply on day 1, cycle 1 and 28 day plus 2 extra day supply at the beginning of each cycle thereafter. 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
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Page 62 
APPENDIX B:  SCHEDULE OF ASSESSMENTS FOR CAPOX ARM (ARM C) 
Tests & Procedures
Pre-Study 
Evaluation
End of Study Visit
Week
0
1
4
Day
up to 9 days 
before 1st dose 
of BBI608 
[-]5
1
22
At least 30 days from 
last BBI608 dose
Written informed consent1
X
Medical history
X
Physical examination
X
X
Serum pregnancy test
X
Karnofsky performance status score
X
X
X
X
X
Vital signs, Weight
X
X
X
X
X
Hematology2
X
X
X
X
Biochemistry2
X
X
X
X
Urinalysis2
X
X
X
X
12-Lead electrocardiogram
X
X
X
Tumor markers (if applicable)2
X
X
Tumor biopsy (if applicable)3
X
Pharmacokinetics
X
X
Tumor measurement & staging4,5,6
X7
X
Concomitant medications
X
X
X
X
X
Adverse events8
X
X
X
Oxaliplatin administration9
X
X
Dispense BBI60810
X
X
Dispense capecitabine11
X
Additional Cycles
On Study Evaluations (+/- 2 days)
X
1
1
Cycle 1
X
X
X
X
Scheduled according to 
specific cycle
X
X
X
X
X
X
X
 
1. 
Written informed consent may be obtained up to 1 month prior to first dose of BBI608     
2. 
Refer to Section 6.3 for description of laboratory assessments. 
3. 
Archival Tissue samples will be obtained per Appendix G once the patient has been enrolled. 
4. 
Including tumor measurements, following RECIST 1.1.  
5. 
At the end of cycle 2 and every other cycle thereafter, assessments must be made utilizing the same imaging method as baseline 
6. 
If at any time during the tumor evaluation visits either a partial or complete response is observed, the same radiographic study should be repeated within four weeks for confirmation of response. 
7. 
Unless CT/MRI has been performed within last three weeks. 
8. 
Patients will be followed until resolution of any drug-related AE or SAE occurring during the study or within 30 days of last BBI608 administration. 
9. 
Oxaliplatin will be administered every 3 weeks 
10. BBI608 will be dispensed in a 5-day plus 2 extra day supply on day [-]5, 28 day supply on day 1, cycle 1 and 28 day plus 2 extra day supply at the beginning of each cycle thereafter. 
11. The appropriate amount of capecitabine will be dispensed at the start of a given cycle 
 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
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Page 63 
. 
APPENDIX C:  SCHEDULE OF ASSESSMENTS FOR FOLFIRI WITH OR WITHOUT BEVACIZUMAB OR IRINOTECAN (ARMS D, E OR G)  
Tests & Procedures
Pre-Study 
Evaluation
End of Study Visit
Week
0
1
3
3
Day
up to 9 days 
before 1st dose 
of BBI608 
[-]5
1
15
15
At least 30 days from 
last BBI608 dose
Written informed consent1
X
Medical history
X
Physical examination
X
X
Serum pregnancy test
X
Karnofsky performance status score
X
X
X
X
X
X
Vital signs, Weight
X
X
X
X
X
X
Hematology2
X
X
X
X
X
Biochemistry2
X
X
X
X
Urinalysis2
X
X
X
X
12-Lead electrocardiogram
X
X
X
Tumor markers (if applicable)2
X
X
Tumor biopsy (if applicable)3
X
Pharmacokinetics4
X
X
Tumor measurement & staging5,6,7
X8
X
Concomitant medications
X
X
X
X
X
X
Adverse events9
X
X
X
X
FOLFIRI  ± Bevacizumab or 
Irinotecan10
X
X
X
Dispense BBI60811
X
X
X
X
X
X
X
X
X
X
X
X
X
Additional Cycles
On Study Evaluations (+/- 2 days)
X
1
1
Cycle 1
 
1. 
Written informed consent may be obtained up to 1 month prior to first dose of BBI608.     
2. 
Refer to Section 6.3 for description of laboratory assessments. 
3. 
Archival Tissue samples will be obtained per Appendix G once the patient has been enrolled. 
4. 
Pharmacokinetic analysis will be collected from study arms D and E only. 
5. 
Including tumor measurements, following RECIST 1.1.  
6. 
At the end of cycle 2 and every other cycle thereafter, assessments must be made utilizing the same imaging method as baseline 
7. 
If at any time during the tumor evaluation visits either a partial or complete response is observed, the same radiographic study should be repeated within four weeks for confirmation of response. 
8. 
Unless CT/MRI has been performed within last three weeks. 
9. 
Patients will be followed until resolution of any drug-related AE or SAE occurring during the study or within 30 days of last BBI608 administration. 
10. FOLFIRI with or without bevacizumab or irinotecan will be administered as per standard schedule. 
11. BBI608 will be dispensed in a 5-day plus 2 extra day supply on day [-]5, 28 day supply on day 1, cycle 1 and 28 day plus 2 extra day supply at the beginning of each cycle thereafter. 
 


 
64 
 
APPENDIX D:  SCHEDULE OF ASSESSMENTS FOR REGORAFENIB (ARM F) 
Tests & Procedures
Pre-Study 
Evaluation
End of Study Visit
Week
0
1
3
Day
up to 9 days 
before 1st dose 
of BBI608 
[-]5
1
15
At least 30 days from 
last BBI608 dose
Written informed consent1
X
Medical history
X
Physical examination
X
X
Serum pregnancy test
X
Karnofsky performance status score
X
X
X
X
X
Vital signs, Weight
X
X
X
X
X
Hematology2
X
X
X
X
Biochemistry2
X
X
X
X
Urinalysis2
X
X
X
X
12-Lead electrocardiogram
X
X
X
Tumor markers (if applicable)2
X
X
Tumor biopsy (if applicable)3
X
Pharmacokinetics
X
X
Tumor measurement & staging4,5,6
X7
X
Concomitant medications
X
X
X
X
X
Adverse events8
X
X
X
Dispense BBI6089
X
X
Dispense regorafenib10
X
X
X
X
X
X
X
X
X
X
X
X
Additional Cycles
On Study Evaluations (+/- 2 days)
X
1
1
Cycle 1
 
1.Written informed consent may be obtained up to 1 month prior to first dose of BBI608     
2.Refer to Section 6.3 for description of laboratory assessments. 
3.Archival Tissue samples will be obtained per Appendix G once the patient has been enrolled. 
4.Including tumor measurements, following RECIST 1.1.  
5.At the end of cycle 2 and every other cycle thereafter, assessments must be made utilizing the same imaging method as baseline 
6.If at any time during the tumor evaluation visits either a partial or complete response is observed, the same radiographic study should be repeated within four weeks for confirmation of response. 
7.Unless CT/MRI has been performed within last three weeks. 
8.Patients will be followed until resolution of any drug-related AE or SAE occurring during the study or within 30 days of last BBI608 administration. 
9.BBI608 will be dispensed in a 5-day plus 2 extra day supply on day [-]5, 28 day supply on day 1, cycle 1 and 28 day plus 2 extra day supply at the beginning of each cycle thereafter. 
10.The appropriate amount of regorafenib will be dispensed at the start of a given cycle 


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June 23rd, 2017 
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Amendment #4 
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Page 65 
 
APPENDIX E:  PERFORMANCE STATUS 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory.  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. 
70 
Cares for self, unable to 
carry on normal activity or 
to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, 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. 
50 
Requires considerable 
assistance and frequent 
medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special 
care and assistance. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not 
imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


Boston Biomedical, Inc  
 
June 23rd, 2017 
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Amendment #4 
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Page 66 
APPENDIX F:  PHARMACOKINETIC STUDIES 
 
Instructions for Collecting and Processing Blood PK Samples 
 
Sampling to define the plasma pharmacokinetics of BBI608 will be performed all patients 
enrolled in each combination arm of the study.  For the FOLFOX6 and FOLFIRI arms (with 
and without bevacizumab), PK samples are taken on Days 1-2 and 15-16 of cycle 1. For the 
CAPOX arm, samples are taken on Days 1-2 and 22-23 of cycle 1. For the regorafenib arm, 
samples are taken on Days 1-2 and 15-16 of cycle 1. For the irinotecan arm, PK samples will 
not be collected. The sampling schedules and summary of procedures that are to be used to 
establish times, collect samples, and process specimens for storage prior to analysis, to insure 
the acquisition of accurate pharmacokinetic data, are described below.  The sampling 
schedules have been devised to accommodate treatment on an outpatient basis.  Dosing of the 
first dose of drug (on day [-] 5) should be started on a Wednesday or Thursday.  
 
Before starting the BBI608 administration, place a large gauge peripheral catheter (e.g., 19 or 20 
gauge angiocath straight set with T-connector, or similar IV access device) within a vein in the 
arm of the subject for the collection of pharmacokinetic blood samples.  Patency of the 
sampling catheter should be maintained between blood draws using either a heparin lock 
(e.g., 10 U/mL in normal saline) or a slow drip of Normal Saline for Injection, USP (e.g., 10 
mL/hr).  Blood may be obtained directly by venipuncture on days when only a single 
pharmacokinetic blood specimen is scheduled for collection.  When sampling through the 
peripheral catheter, begin to clear the catheter approximately 1 minute before the specified 
sample time by withdrawing the lock solution and approximately 0.5 mL of blood into a 
syringe.  Remove and properly dispose the syringe used to clear the catheter. 
 
A battery-powered digital timer/stopwatch programmed to operate continuously as a 24-hr 
clock will be used to accurately monitor drug administration and sample collection times.  
The same timer must be allowed to run without interruption until the last blood specimen has 
been obtained from the subject during the first cycle of therapy.  Timer readings will be 
noted at the precise time that the administration is started as well as at the beginning and 
ending times of the blood sample collection intervals.  Readings of the digital timer must be 
directly recorded on a copy of the appropriate Pharmacokinetic Dosing and Blood Collection 
Time Form.  All blood samples should be drawn within ± 3 minutes of the desired time.   
 
Please note that blood and plasma must be protected from direct exposure to light and all 
sample processing procedures are to be performed in a room with indirect lighting.  The 
volume of blood collected for each pharmacokinetic sample will be 3 mL.  This volume has 
shown to be adequate for the pharmacokinetic assay.  Samples are to be collected in plastic 
Vacutainer plasma collection tubes.  Immediately wrap the tube with aluminum foil to 
protect it from exposure to light.  Promptly mix the plasma collection tube by gently 
inverting 6-times, then place it on wet ice, and centrifuge (1,100-1,300 x g, 10 min, 4°C) 
within 5-10 minutes after collection.  Separate the plasma from the blood cells pellet (please 
see Blood Cell Pellet section directly following for instructions for this portion of the sample) 
using a pipette and transfer approximately equal volumes into three self-standing opaque 


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June 23rd, 2017 
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Amendment #4 
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Page 67 
amber polypropylene microcentrifuge cryogenic tubes with external threads.  Affix a pre-
printed label (protocol number, subject initials, subject number, sample collection date and 
time) to the cryotube, oriented lengthwise toward the upper part of the tube.  Hand-written 
information on sample tube labels is absolutely prohibited. Completely cover the label with 
protective cryogenic freezer tape.  Place the tube on crushed dry-ice until stored in a freezer 
maintained at ≤ -70°C.  Any deviation from the sample collection time needs to be 
documented in the study subjects’ case report forms and in their study binder. 
 
The total volume of blood collected for pharmacokinetic studies, 84-120 mL, represents < 
5% of the total blood volume for a 60 kg subject, during a 28-day treatment cycle.  As 
pharmacokinetic data becomes available during the course of the trial, it may be necessary to 
modify the number of samples or the times at which they are collected to more accurately 
define the plasma concentration-time profile of the drug.  However, the cumulative volume 
of blood collected for pharmacokinetic sampling will not exceed 240 mL, or approximately 
5% of the total volume of a 60 kg subject during the first 4 weeks of study treatment.   
 
Computer files for dose administration and sample collection time forms and specimen tube 
labels will be provided to the lab personnel in charge of labeling.  The PK_Tube_Label files 
are templates, and the files are copied to user computers and the limited information 
pertaining to each subject studied, typically the subject entry no., is added by editing the 
computer file, and subsequently printed onto adhesive-backed labels.  Hand-written 
information on sample tube labels is absolutely prohibited.  There are separate sets of labels 
for blood collection vials and sample storage tubes.  Blood collection vials should be pre-
labeled.   
Time points will be determined as the difference between the midpoint of the blood 
collection interval and starting time of dose administration.  Concentration-time profiles of 
BBI608 will be analyzed by non-compartmental methods and/or nonlinear least squares 
regression using WinNonlin (Scientific Consulting, Inc.).  Pharmacokinetic parameters and 
variables will be calculated according to standard equations. 
 
Blood Cell Pellet 
 In addition to the plasma samples obtained for pharmacokinetic analysis (as outlined above), 
the  blood cell pellet that results from centrifuging the patient blood samples is also 
requested. The cell fraction is required for comprehensive BBI608 PK and biomarker 
assessment.  
At the Cycle 1, Day 1 (C1D1) visit, blood cells should be saved from the first four PK 
samples (-5, 60, 120, and 180 minutes) and must be shipped to Boston Biomedical within 24 
hours—preferably on the same day the blood is drawn. To isolate the blood cells, retain the 
EDTA vacutainers once the plasma has been poured off and store these samples either on ice 
or at 4 °C. If, for any reason, the C1D1 cells fractions either cannot be obtained or are 
unsuitable for analysis by the sponsor, the cell fractions from the equivalent first four PK 
samples on the second PK day in Cycle 1 may be shipped instead. The samples should then 
be shipped on wet ice to Boston Biomedical. 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
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Page 68 
Pharmacokinetic Sample Collection: FOLFOX6 and FOLFIRI Arms (±Bevacizumab) (CYCLE 
1 ONLY) 
 
Day 
Procedure 
Sample No. 
Desired Time 
1 
 
 
Draw blood sample 
PK-01 
-5 min 
First daily  BBI608 dose 
 
0 
Draw blood sample 
PK-02 
60 min 
Draw blood sample 
PK-03 
120 min 
Draw blood sample 
PK-04 
180 min 
Begin Combination Regimen 
Administrationa 
 
180 min 
Draw blood sample 
PK-05 
240 min 
Draw blood sample 
PK-06 
300 min 
Draw blood sample 
PK-07 
360 min 
Draw blood sample 
PK-08 
420 min 
Draw blood sample 
PK-09 
480 min 
Draw blood sample 
PK-10 
540 min 
Draw blood sample 
PK-11 
600 min 
Draw blood sample 
PK-12 
660 min 
2 
Draw blood sample 
PK-13 
24 hours 
Draw blood sample 
PK-14 
30-32 hoursb 
Day 
Procedure 
Sample No. 
Desired Time 
15 
 
Draw blood sample 
PK-15 
-5 min 
First daily BBI608 dose 
 
0 
Draw blood sample 
PK-16 
60 min 
Draw blood sample 
PK-17 
120 min 
Draw blood sample 
PK-18 
180 min 
Begin Combination Regimen 
Administrationa 
 
180 min 
Draw blood sample 
PK-19 
240 min 
Draw blood sample 
PK-20 
300 min 
Draw blood sample 
PK-21 
360 min 
Draw blood sample 
PK-22 
420 min 
Draw blood sample 
PK-23 
480 min 
Draw blood sample 
PK-24 
540 min 
Draw blood sample 
PK-25 
600 min 
Draw blood sample 
PK-26 
660 min 
16 
Draw blood sample 
PK-27 
24 hours 
Draw blood sample 
PK-28 
30-32 hoursb 
aFOLFOX6/FOLFIRI ±Bevacizumab infusion  
bPK draw can occur anywhere in this timeframe, however exact time of draw must be 
recorded 


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June 23rd, 2017 
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Amendment #4 
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Page 69 
 
Pharmacokinetic Sample Collection:  CAPOX arm (CYCLE 1 ONLY) 
 
Day 
Procedure 
Sample No. 
Desired Time 
1 
 
 
Draw blood sample 
PK-01 
-5 min 
First daily  BBI608 dose 
 
0 
Draw blood sample 
PK-02 
60 min 
Draw blood sample 
PK-03 
120 min 
Draw blood sample 
PK-04 
180 min 
Begin Combination Regimen 
Administration* 
 
180 min 
Draw blood sample 
PK-05 
240 min 
Draw blood sample 
PK-06 
300 min 
Draw blood sample 
PK-07 
360 min 
Draw blood sample 
PK-08 
420 min 
Draw blood sample 
PK-09 
480 min 
Draw blood sample 
PK-10 
540 min 
Draw blood sample 
PK-11 
600 min 
Draw blood sample 
PK-12 
660 min 
2 
Draw blood sample 
PK-13 
24 hours 
Day 
Procedure 
Sample No. 
Desired Time 
22 
 
Draw blood sample 
PK-15 
-5 min 
First daily BBI608 dose 
 
0 
Draw blood sample 
PK-16 
60 min 
Draw blood sample 
PK-17 
120 min 
Draw blood sample 
PK-18 
180 min 
Begin Combination Regimen 
Administration* 
 
180 min 
Draw blood sample 
PK-19 
240 min 
Draw blood sample 
PK-20 
300 min 
Draw blood sample 
PK-21 
360 min 
Draw blood sample 
PK-22 
420 min 
Draw blood sample 
PK-23 
480 min 
Draw blood sample 
PK-24 
540 min 
Draw blood sample 
PK-25 
600 min 
Draw blood sample 
PK-26 
660 min 
23 
Draw blood sample 
PK-27 
24 hours 
*Oxaliplatin IV infusion and capecitabine oral administration 
 
 
 


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June 23rd, 2017 
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Page 70 
Pharmacokinetic Sample Collection:  Regorafenib arm (CYCLE 1 ONLY) 
 
Day 
Procedure 
Sample No. 
Desired Time 
1 
 
 
Draw blood sample 
PK-01 
-5 min 
First daily  BBI608 dose 
 
0 
Draw blood sample 
PK-02 
60 min 
Draw blood sample 
PK-03 
120 min 
Draw blood sample 
PK-04 
180 min 
Administer regorafenib 
 
180 min 
Draw blood sample 
PK-05 
240 min 
Draw blood sample 
PK-06 
300 min 
Draw blood sample 
PK-07 
360 min 
Draw blood sample 
PK-08 
420 min 
Draw blood sample 
PK-09 
480 min 
Draw blood sample 
PK-10 
540 min 
Draw blood sample 
PK-11 
600 min 
Draw blood sample 
PK-12 
660 min 
2 
Draw blood sample 
PK-13 
24 hours 
Day 
Procedure 
Sample No. 
Desired Time 
15 
 
Draw blood sample 
PK-15 
-5 min 
First daily BBI608 dose 
 
0 
Draw blood sample 
PK-16 
60 min 
Draw blood sample 
PK-17 
120 min 
Draw blood sample 
PK-18 
180 min 
Administer regorafenib 
 
180 min 
Draw blood sample 
PK-19 
240 min 
Draw blood sample 
PK-20 
300 min 
Draw blood sample 
PK-21 
360 min 
Draw blood sample 
PK-22 
420 min 
Draw blood sample 
PK-23 
480 min 
Draw blood sample 
PK-24 
540 min 
Draw blood sample 
PK-25 
600 min 
Draw blood sample 
PK-26 
660 min 
16 
Draw blood sample 
PK-27 
24 hours 
 
 
 
 
 
 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
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Page 71 
APPENDIX G: TUMOR BIOPSIES 
 
Instructions for Collecting, Processing and Shipping Samples 
 
Archival tissues: 
 
Archival tissue samples should be collected from all patients enrolled in the clinical trial if 
they are available.  Archive tissue labels should be coded with the protocol number, study 
site number, the patient’s initials and the patient number.  Paraffin embedded tissue blocks or 
prepared tissue slides should be shipped by courier to Boston Biomedical at the address listed 
below.  Tissue blocks are preferred; however, if blocks are not available, 10-15 unstained, 
positively charged, 5 micron thickness slides may be sent. 
 
 
Fresh Tumor Biopsies: 
 
Tumor biopsies will be collected for immunohistopathology-based analysis of the target and 
its downstream genes and for the analysis of the effect of BBI608 on cancer stem cells.  
These samples will be used for research purposes only.  Tumor biopsies for analysis should 
be collected by core biopsy or minimally invasive procedures.  Tumor specimen samples 
should be processed sterilely into three parts: fixed, frozen, and fresh.   
 
Fixed Tumor Biopsies for Immunohistochemistry:  
 
The sample should be processed to yield paraffin embedded tissues using the study site’s 
standard operating procedures.  The samples should be labeled and coded with the protocol 
number, study site number, the patient’s initials, the patient number and the sample collection 
date and time. The paraffin embedded tissue blocks should be shipped to Boston Biomedical 
at the address listed below. 
 
Fresh and Frozen Tumor Biopsy Specimens for Cancer Stem Cell Assays: 
 
Tumor biopsies for the analysis of the effect of BBI608 on cancer stem cells should be 
collected by core biopsy or similar minimally invasive procedures.  Once the biopsy tissue is 
obtained, half of the biopsy tissue should be immediately placed in sterile fashion into CSC 
transport media provided by Boston Biomedical, stored and shipped at 4ºC.  Overnight 
shipment should be arranged on the same day as the biopsy is performed.  A label should be 
affixed to all sample tubes containing with the protocol number, study site number, the 
patient’s initials, the patient number and the sample collection date and time.  The other half 
should be immediately snap-frozen in liquid nitrogen, and then transferred to a 
polypropylene microcentrifuge cryogenic tube. The tissue sample should then be stored at ≤ -
70ºC until being shipped to Boston Biomedical on dry ice to the address listed below.    
 
 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 72 
Shipping information: 
 
Please ship all tumor samples to the following address: 
 
Youzhi Li, M.D. 
Boston Biomedical, Inc. 
640 Memorial Drive 
Cambridge, MA 02139 USA 
Phone: 617-674-6800 
Fax: 617-674-8661 
 
On the day that specimens are sent to Boston Biomedical, please contact Boston Biomedical 
by phone, fax or email to notify what is being sent and when the shipment is expected to 
arrive. 
 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 73 
 
SPONSOR SIGNATURE 
 
Study Title: 
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Standard Chemotherapies in Adult Patients with 
Advanced Gastrointestinal Cancer  
Study Number: 
BBI608-246 
Amendment 1: 
September 26th, 2015 
Amendment 2: 
August 17th, 2016 
Amendment 3: 
December 6th, 2016 
Amendment 4: 
June 23rd, 2017 
 
This clinical study protocol is subject to critical review and has been approved by the Sponsor.  The 
following personnel contributed to writing and/or approving this protocol: 
 
 
Signed: ____________________Date: _____________________ 
 
Laura Borodyansky, MD  
Vice President of Clinical Development & Pharmacovigilance 
Boston Biomedical, Inc.  
 
 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 74 
 
INVESTIGATOR’S SIGNATURE 
 
Study Title: 
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Standard Chemotherapies in Adult Patients with 
Advanced Gastrointestinal Cancer  
Study Number: 
BBI608-246  
Amendment 1: 
September 26th, 2015 
Amendment 2: 
August 17th, 2016 
Amendment 3: 
December 6th, 2016 
Amendment 4: 
June 23rd, 2017 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
 
Printed Name: _____________________________________ 
 
 
 
Signature: ___________________Date: ____________________ 
 
 
 


Boston Biomedical, Inc  
 
June 23rd, 2017 
BBI608-246 
 
Amendment #4 
Confidential 
 
Page 75 
REFERENCES 
Bennouna, J., Sastre, J., Arnold, D., Osterlund, P., Greil, R., Van Cutsem, E., von Moos, R., Vietez, J.M., 
Bouche, O., Borg, C., Steffens, C.C., Alonso-Orduna, V., Schlichting, C., Reyes-Rivera, I., Bendahmane, T.A., 
Kubicka, T., et al. (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer 
(ML18147): a randomized phase 3 trial. The Lancet Onc 14, 29-37. 
Boman, B.M., and Wicha, M.S. (2008). Cancer stem cells: a step toward the cure. J. Clin. Oncol. Off. J. Am. 
Soc. Clin. Oncol. 26, 2795–2799. 
Clevers, H. (2011). The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319. 
Kawada, M., Seno, H., Uenoyama, Y., Sawabu, T., Kanda, N., Fukui, H., Shimahara, Y., and Chiba, T. (2006). 
Signal transducers and activators of transcription 3 activation is involved in nuclear accumulation of beta-
catenin in colorectal cancer. Cancer Res. 66, 2913–2917. 
Lobo, N.A., Shimono, Y., Qian, D., and Clarke, M.F. (2007). The biology of cancer stem cells. Annu. Rev. Cell 
Dev. Biol. 23, 675–699. 
Magee, J.A., Piskounova, E., and Morrison, S.J. (2012). Cancer stem cells: impact, heterogeneity, and 
uncertainty. Cancer Cell 21, 283–296. 
Morikawa, T., Baba, Y., Yamauchi, M., Kuchiba, A., Nosho, K., Shima, K., Tanaka, N., Huttenhower, C., 
Frank, D.A., Fuchs, C.S., et al. (2011). STAT3 expression, molecular features, inflammation patterns, and 
prognosis in a database of 724 colorectal cancers. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 17, 1452–
1462. 
O'Neil, B, H., Hubbard, J.M., Starodub, A., Jonker, D.J., Edenfield, W.J., El-Rayes, B.F., Halfdanarson, T.R., 
Ramanathan, R.K., Pitot, H.C., Britten, C.D., Adesunloye, B., Grothey, A., Borodyansky, L., Li, C. (2016) 
Phase Ib extension study of cancer stemness inhibitor BBI608 (napabucasin) administered in combination with 
FOLFIRI +/- bevacizumab in patients with advanced colorectal cancer. J. Clin Oncol 34, suppl; abstr 3564. 
Schmalhofer, O., Brabletz, S., and Brabletz, T. (2009). E-cadherin, beta-catenin, and ZEB1 in malignant 
progression of cancer. Cancer Metastasis Rev. 28, 151–166. 
Singh, A., and Settleman, J. (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the 
war on cancer. Oncogene 29, 4741–4751. 
White, B.D., Chien, A.J., and Dawson, D.W. (2012). Dysregulation of Wnt/β-catenin signaling in 
gastrointestinal cancers. Gastroenterology 142, 219–232. 
 
 
 

SAP_001.pdf: 
BBI CONFIDENTIAL
1
SAP BBI608-246
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Standard Chemotherapies in Adult Patients with 
Advanced Gastrointestinal Cancer
Statistical Analysis Plan
(SAP)
Version: 4.0
Author: Emma Foos (Biostatistics – Cambridge)
Date:
12-OCT-2020
Emma Foos (Biostatistics – Cambridge)


BBI CONFIDENTIAL
2
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Version 
1.0
August 
2, 
2017
Emma Foos
Statistical Analysis Plan 
Version 
2.0
August 30, 
2018
Emma Foos
x
Laboratory variables and 
analysis have been edited. 
x
Censoring rules have been 
edited for PFS
Version 
3.0
July 
10, 
2019
Emma Foos
x
Analysis sets have been edited
x
Study Day has been added 
x
Methods for handling missing 
data has been edited
x
Details regarding the efficacy 
endpoint analyses have been 
added
x
Details regarding the TEAE 
analysis have been edited
x
Analysis for AECRs have been 
added
x
Laboratory analysis has been 
edited
x
Karnofsky performance status 
analysis has been added
x
ECG analysis has been edited
x
Physical exam analysis has 
been added
x
PFS censoring hierarchy has 
been edited
Emma Foos
Emma Foos
Emma Foos


BBI CONFIDENTIAL
3
Version 
3.1
February 24,
2020
Emma Foos
x
BBI608 has been changed to 
napabucasin
x
Extent of Exposure section has 
been edited
x
Analysis for treatment 
discontinuation due to TEAE 
has been added
x
Two additional AECRs have 
been added
x
Additional summarization of 
concomitant medications has 
been added
x
Prior therapy analysis has been 
edited
x
E-dish plot has been added
x
Concurrent medical conditions 
summary has been added
Version 
4.0
October 12,
2020
Emma Foos
x
Removed mixed effects model 
assessing the effect of 
bevacizumab on napabucasin 
PK with the coadministration 
of FOLFOX6 or FOLFIRI
Emma Foos
Emma Foos


BBI CONFIDENTIAL
4
STATISTICAL ANALYSIS PLAN APPROVAL
Author:
_________________________________________ Date: _____/_____/_________
Emma Foos
Senior Biostatistician, Sumitomo Dainippon Pharma Oncology, Inc.
Approved by:
_________________________________________ Date: _____/_____/_________
Suha Sari, PhD
Director, Biostatistics, Sumitomo Dainippon Pharma Oncology, Inc.
_________________________________________ Date: _____/_____/_________
Matthew Hitron, MD
Executive Medical Director, Clinical Research, Sumitomo Dainippon Pharma Oncology,
Inc.
_________________________________________ Date: _____/_____/_________
Tess Schmalbach, MD, PhD
Napabucasin Safety Lead, Pharmacovigilance, Sumitomo Dainippon Pharma Oncology,
Inc.
____
___
_____
___
_ ______
_
___
Matthew Hitron, MD
Suha Sari, PhD
Emma Foos
Senior Biostatistician,
Tess Schmalbach, MD, PhD
__
________
_
__
_____
_____
___
_____
________
_________________________ 
___
___
__
_______
____
____
___
______


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
5
Contents 
1. AMENDMENTS FROM PREVIOUS VERSION(S) .........................................10 
2. INTRODUCTION ...............................................................................................10 
2.1. Study Design ...........................................................................................10 
2.2. Study Populations....................................................................................13 
2.3. Determination of Sample Size.................................................................13 
2.4. Study Objectives......................................................................................14 
2.4.1. Primary Objectives .....................................................................14 
2.4.2. Secondary Objectives .................................................................14 
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS .15 
3.1. Primary Endpoints...................................................................................15 
3.1.1. Phase Ib.......................................................................................15 
3.1.2. Phase II .......................................................................................15 
3.2. Secondary Endpoints...............................................................................15 
3.2.1. Phase Ib.......................................................................................15 
3.2.2. Phase II .......................................................................................15 
3.3. Safety Endpoints......................................................................................16 
3.3.1. Adverse Events, Laboratory Test Results, and Other Safety 
Endpoints in Phase Ib and Phase II ........................................16 
3.4. Covariates................................................................................................16 
4. INTERIM ANALYSES.......................................................................................16 
5. ANALYSIS SETS ...............................................................................................16 
5.1. Full Analysis Set .....................................................................................16 
5.2. Response Analysis Set.............................................................................16 
5.3. PK Analysis Set.......................................................................................16 
5.4. Pharmacodynamics/Biomarker Analysis Set ..........................................17 
6. DATA HANDLING ............................................................................................17 
6.1. Methods for Handling Missing Dates .....................................................17 
6.2. Definition of Baseline Values .................................................................19 
6.3. Study Day................................................................................................19 
6.4. Visit Windows.........................................................................................19 
6.5. Dropouts..................................................................................................19 


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Statistical Analysis Plan
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6
6.6. Pharmacokinetics.....................................................................................19 
6.7. Pharmacodynamic Parameters ................................................................20 
7. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........20 
7.1. Statistical Methods ..................................................................................20 
7.1.1. Analysis for Time to Event Data ................................................20 
7.1.2. Analysis for Binary Data ............................................................20 
7.1.3. Analysis for Continuous Data.....................................................20 
7.2. Statistical Analyses..................................................................................21 
7.2.1. Standard Analysis .......................................................................21 
7.2.2. Analysis for Primary Endpoint ...................................................25 
7.2.3. Analyses for Secondary Endpoints.............................................26 
7.2.4. Analyses for Other Endpoints.....................................................28 
8. REFERENCES ....................................................................................................33 
8.1. Appendix 1.1 Further Definition of Endpoints .......................................34 
8.2. Appendix 1.2 Censoring for Time to Event Data....................................36 


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
7
ABBREVIATIONS AND DEFINITIONS 
AE
Adverse event
AECR
Adverse Event of Clinical Relevance
ALT
Alanine transaminase (SGPT)
ANOVA
Analysis of variance
AP
Alkaline phosphatase
AST
Aspartate transaminase (SGOT)
AUC
Area under the time-concentration curve
BID
Twice daily
BSA
Body surface area
BUN
Blood urea nitrogen
BLQ
Below the limit of quantification
CBC
Complete blood count
CDER
Center for Drug Evaluation and Research
Cmax
Maximum plasma drug concentration
Cmin
Minimum plasma drug concentration
CFR
Code of Federal Regulations
CI
Confidence interval
CR
Complete response
CRC
Colorectal Cancer 
CRF
Case report form
CT
Computed tomography
CV
Coefficient of variation
CTCAE
Common terminology criteria for adverse events
DCR
Disease Control Rate
DLT
Dose limiting toxicity
ECG
Electrocardiogram
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
GI
Gastrointestinal
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
HCC
Hepatocellular Carcinoma 


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
8
Hct
Hematocrit
HED
Human equivalent dose
Hgb
Hemoglobin
HGF
Hepatocyte growth factor
HIPAA
Health Information Portability and Accountability Act
IC50
Inhibitory concentration, 50%
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
LD
Longest diameter
LDH
Lactic dehydrogenase
MR
Minor response
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NE
Not Evaluable
NOAEL
No observable adverse effect level
NOEL
No observable effect level
ORR
Objective response rate
OS
Overall Survival
PD
Progressive disease
PFS
Progression Free Survival
PK
Pharmacokinetic
PR
Partial response
QD
Once daily
RECIST
Response evaluation criteria in solid tumors
RP2D
Recommended Phase 2 dose
RBC
Red blood cell (count)
SAE
Serious adverse event
SD
Stable disease
SE
Standard error 
SGOT
Serum glutamic oxaloacetic transaminase (AST)


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
9
SGPT
Serum glutamic pyruvic transaminase (ALT)
SMQ
Standard MedDRA Query
TEAE
Treatment Emergent Adverse Event
Tmax
Time to maximum plasma concentration
TNM Scale
Tumor node metastases scale
ULN
Upper limits of normal
WBC
White blood cell (count)


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
10
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
This is the fourth version of the statistical analysis plan, based on the BBI608-246 protocol 
dated June 23rd, 2017. The major changes in this amendment are replacing BBI608 with 
napabucasin, the analysis sets, addition of study day, details regarding the efficacy endpoint 
analyses, methods for handling missing data, extent of exposure analysis, details regarding 
the TEAE analysis, addition of analysis for AECRs and adding two additional AECRs,
editing of lab analyses, addition of Karnofsky performance status analysis, addition of 
physical exam analysis, editing ECG analysis, editing of PFS censoring hierarchy, adding 
in treatment discontinuation due to TEAE analysis, adding a new summary table for 
concomitant medication using preferred base, editing the summarization of prior therapies,
adding concurrent medical conditions summary, removing mixed effects model assessing 
the effect of bevacizumab on napabucasin PK with the coadministration of FOLFOX6 or 
FOLFIRI, and adding an E-DISH plot.
2. INTRODUCTION 
2.1. Study Design 
Phase Ib
Phase Ib is an open-label study of oral napabucasin administered with either FOLFOX6 
with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, 
regorafenib or irinotecan to patients with advanced GI malignancy. The study is designed 
to explore the safety, tolerability and pharmacokinetics of napabucasin, and to define a 
recommended Phase 2 dose (RP2D) of napabucasin when administered in combination 
with each one of the above regimens (except for irinotecan study arm for which RP2D in 
combination with napabucasin has been established).


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
11
Initially, 3 patients will be enrolled in each combination arm (except for the irinotecan 
study arm for which enrollment will begin with the expansion phase skipping dose-limiting 
toxicity (DLT) period assessment since the RP2D for napabucasin in combination with 
irinotecan has been established) at a napabucasin dose level of 240 mg twice daily (480 mg 
total daily dose—Cohort I).  If 0 out of 3 patients experience a DLT, then the napabucasin
dose will be escalated to 480 mg twice daily (960 mg total daily dose—Cohort II) and 6 
patients will be enrolled at this dose level. If 1 out of 3 patients in the 240 mg twice daily 
cohort experience a DLT, then an additional 3 patients will be enrolled in that arm.  If a 
DLT occurs in ≥2 of the 6 patients in an arm, then the napabucasin dose will be reduced to 
160 mg twice daily (320 mg total daily dose—Cohort Ib) and 6 patients will be enrolled at 
this does level. 
If <1 of 6 patients experience a DLT at the 240 mg twice daily dose level, then napabucasin
dose will be escalated to 480 mg twice daily (960 mg total daily dose) and 6 patients will 
be enrolled at this dose level. If ≤1 out of 6 patients experiences a DLT at 480 mg twice 
daily, this dose level will be considered the RP2D for napabucasin in that combination. 
If ≥2 out of 6 patients experience a DLT at 480 mg twice daily, then RP2D will be declared 
as the next lowest dose level at which ≤1 out of 6 patients experiences a DLT. 
Cycles of therapy will consist of the patient taking napabucasin daily in combination 
therapy for 28 days.  Tumor assessments will be performed every two cycles (8 weeks), or 
as otherwise clinically indicated.
Dose escalation would be performed using patient cohorts as shown in Table 1.


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
12
Table 1:  Dose Escalation Scheme for Napabucasin
Cohort
Total Daily Dosea (mg)
Number 
of 
Patients
I
480 mg
3 b,c
Ib
320 mg
3 b,d
II
960 mg
6
a.Daily dose must be taken one hour prior to or two hours after 
meals
b If a napabucasin-related DLT is seen in a 3-patient cohort an 
additional 3 patients will be enrolled at the same dose
cIf ≥2 of 6 patients experience a napabucasin-related DLT, 
then the napabucasin dose will be reduced to 160 mg twice 
daily (total daily dose of 320 mg—Cohort Ib) and 6 patients 
will be enrolled at this dose level. 
dIf ≥2 patients experience a napabucasin-related DLT at this 
dose level, the arm will be closed to accrual.
The RP2D for a given combination arm is defined as the dose level at which no more than 
1 patient with a DLT is observed among 6 patients for each combination.  Once the RP2D 
has been reached for a given combination arm based on DLT assessment rules outlined 
above, up to 15 additional evaluable patients may be enrolled at RP2D.  If a patient drops-
out another patient may be enrolled such that there are 15 evaluable patients available for 
analysis. An additional 20 evaluable patients will be enrolled on the hepatocellular 
carcinoma, cholangiocarcinoma, gastric/GEJ, esophageal or pancreatic adenocarcinoma 
disease cohorts.  Up to an additional 50 evaluable FOLFIRI/XELIRI-refractory colorectal 
cancer (CRC) patients will be enrolled on the FOLFIRI (with bevacizumab if clinically 
indicated) study arm as an expansion cohort.
Phase II
In Phase II, 50 evaluable FOLFIRI/XELIRI-refractory CRC patients will be enrolled on 
the FOLFIRI study arm (with bevacizumab if clinically indicated) as an expansion cohort. 
FOLFIRI/XELIRI-refractory 
CRC 
patients 
will 
have 
failed 
treatment 
with 
FOLFIRI/XELIRI with or without bevacizumab regimen with failure defined as 
progression of disease during or <3 months after the last dose of FOLFIRI/XELIRI with or 
without bevacizumab.  For the FOLFIRI/XELIRI-refractory CRC patients enrolled on the 
expansion cohort for whom bevacizumab is clinically indicated, bevacizumab 5 mg/kg will 
be administered intravenously following irinotecan/leucovorin infusion. In case of toxicity, 
dose adjustment is permitted.


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
13
In both Phase Ib and Phase II, a study cycle will consist of 28 days of daily administration 
of napabucasin in combination with FOLFOX6 with and without bevacizumab or CAPOX 
or FOLFIRI with and without bevacizumab, regorafenib or irinotecan. Pharmacokinetic 
(PK) and pharmacodynamic assessments will be performed in the first cycle only for each 
drug combination. If there is an indication of drug accumulation, PK assessment can be 
performed for more than two cycles. Safety and tolerability of napabucasin in combination 
with FOLFOX6 with and without bevacizumab or CAPOX or FOLFIRI with and without 
bevacizumab, regorafenib or irinotecan will be assessed for the duration of study treatment 
and for 30 days after the last dose of napabucasin. Evaluation of anti-tumor activity of 
napabucasin in combination with FOLFOX6 with and without bevacizumab or CAPOX or 
FOLFIRI with and without bevacizumab, regorafenib or irinotecan will be performed at 8 
week intervals while patients remain on study according to RECIST 1.1. Patients will have 
confirmatory radiographic scanning within approximately 4 weeks of initial results of 
partial response (PR) or complete response (CR) according to RECIST 1.1. 
2.2. Study Populations 
This study is conducted in patients with advanced solid gastrointestinal malignancies for 
whom treatment with FOLFOX6 with and without bevacizumab, or CAPOX, or 
FOLFIRI with and without bevacizumab, regorafenib or irinotecan is an appropriate 
treatment option in the judgment of physician investigators. Examples of gastrointestinal 
cancers eligible for protocol therapy include the following:
x
Colorectal Cancer (CRC)
x
Hepatocellular Carcinoma (HCC)
x
Pancreatic Adenocarcinoma
x
Cholangiocarcinoma
x
Gastro-esophageal Carcinoma
The study will be conducted at sites in the United States, Canada, and Europe. 
2.3. Determination of Sample Size 
Phase Ib
The sample size for this study was determined by clinical rather than statistical 
considerations.  With cohort sizes of 3 to 6 patients, if the true underlying rates of DLT are 
0.1, 0.2, 0.3, 0.4, and 0.5, there will be 91%, 71%, 49%, 31%, and 17% chances, 
respectively, of escalating to the next full dose.
Phase II
There is no statistical hypothesis testing in the Phase II part of the study. The sample size 
for this phase will use an estimation approach for objective response rate (ORR). If an ORR 


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
14
response rate with FOLFIRI (with bevacizumab if clinically indicated) in combination with 
napabucasin is observed to be 12% with evaluable number of patients of N=50, the 95% 
confidence interval (CI) for the true ORR will be (4.5%, 24.3%) using exact method and 
the corresponding confidence interval length will be 19.8%.  The following table provides 
some examples of the 95% CIs of the true ORR when various ORRs are observed with 
different evaluable numbers of patients.  
N
Observed ORR
95% CI of True 95% CI length
40
10%
(2.8%, 23.7%)
20.9%
40
12%
(3.9%, 26.2%)
22.3%
40
14%
(5.1%, 28.6%)
23.6%
50
10%
(3.3%, 21.8%)
18.5%
50
12%
(4.5%, 24.3%)
19.8%
50
14%
(5.8%, 26.7%)
20.9%
60
10%
(3.8%, 20.5%)
16.7%
60
12%
(5.0%, 23.0%)
17.9%
60
14%
(6.4%, 25.4%)
19.0%
2.4. Study Objectives  
2.4.1. Primary Objectives 
Phase Ib:
To determine the safety, tolerability and recommended Phase 2 dose (RP2D) of 
napabucasin when administered in combination with FOLFOX6 with and without 
bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, regorafenib or 
irinotecan in adult patients with advanced gastrointestinal (GI) cancer.
Phase II:
To assess the objective response rate (ORR) of napabucasin administered in combination 
with FOLFIRI (with bevacizumab if clinically indicated) in patients with 
FOLFIRI/XELIRI-refractory metastatic colorectal cancer (mCRC).
2.4.2. Secondary Objectives 
Phase Ib:
x
To determine the pharmacokinetic profile of napabucasin administered in 
combination with FOLFOX6 with and without bevacizumab or CAPOX or 
FOLFIRI with and without bevacizumab or regorafenib
x
To assess the preliminary anti-tumor activity of napabucasin when administered in 
combination with FOLFOX6 with and without bevacizumab or CAPOX or 
FOLFIRI with and without bevacizumab, regorafenib or irinotecan.


Protocol BBI608-246
Statistical Analysis Plan
BBI CONFIDENTIAL
15
x
To determine the pharmacodynamics (i.e., identify biomarkers) of napabucasin
administered in combination with FOLFOX6 with and without bevacizumab or 
CAPOX, or FOLFIRI with and without bevacizumab, regorafenib or irinotecan.
Phase II:
To assess the disease control rate (DCR), progression free survival (PFS), and overall 
survival (OS) of napabucasin administered in combination with FOLFIRI (with 
bevacizumab if clinically indicated) in patients with FOLFIRI/XELIRI-refractory mCRC.
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS 
3.1. Primary Endpoints 
3.1.1. Phase Ib 
Dose Limiting Toxicities (DLTs): For definition of DLT, see section 4.5 of Protocol [1]
3.1.2. Phase II 
Objective response rate (ORR) of napabucasin administered in combination with 
FOLFIRI (with bevacizumab if clinically indicated) in patients with FOLFIRI/XELIRI-
refractory mCRC, which is defined as the proportion of patients with a documented 
complete response (CR) or partial response (PR) based on RECIST 1.1 as determined 
by the investigator assessment collected in the CRFs, relative to the Response 
Evaluable analysis set (see Table 4 in Appendix 1.1 for Response Criteria).
3.2. Secondary Endpoints 
3.2.1. Phase Ib 
x
PK parameters of napabucasin administered in combination with FOLFOX6 with 
and without bevacizumab or CAPOX or FOLFIRI with and without bevacizumab 
or regorafenib.
x
Objective tumor response, as assessed using the Response Evaluation Criteria in
Solid Tumor (RECIST) version 1.1 (8.1).
x
Pharmacodynamics parameters (or biomarkers in archival tumor tissues), if 
identified appropriately, of napabucasin administered in combination with 
FOLFOX6 with and without bevacizumab or CAPOX, or FOLFIRI with and 
without bevacizumab, regorafenib or irinotecan. 
3.2.2. Phase II 
x
Disease control rate (DCR), progression free survival (PFS), and overall survival 
(OS) of napabucasin
administered in combination with FOLFIRI (with 


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bevacizumab if clinically indicated) in patients with FOLFIRI/XELIRI-refractory 
mCRC (see 8.1 for Response Criteria and PFS/OS definitions).
3.3. Safety Endpoints 
3.3.1. Adverse Events, Laboratory Test Results, and Other Safety Endpoints in Phase 
Ib and Phase II 
x
Adverse Events (AEs) as characterized by type, frequency, severity (as graded by
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI
CTCAE] version 4.0), seriousness, and relationship to study therapy
x
Laboratory test results as characterized by type, change from baseline, and severity 
(as graded by National Cancer Institute Common Terminology Criteria for Adverse 
Events [NCI CTCAE] version 4.0)
x
Other safety endpoints include physical examination, Karnofsky performance 
score, electrocardiogram (ECG) and vital signs data.
3.4. Covariates  
Demographic and baseline disease characteristics may be considered as covariates in 
population PK, PK/PD (biomarker) and anti-tumor efficacy exploratory analyses. 
4. INTERIM ANALYSES  
No formal interim analyses are planned for this study
5. ANALYSIS SETS 
5.1. Full Analysis Set 
The full analysis set (FAS) includes all patients who received at least one dose of any study 
drug.  
5.2. Response Analysis Set 
The response data will be summarized for all patients who receive at least one cycle of 
study drug, have measurable disease at baseline, and at least one post baseline response 
assessment. Initiation of therapy is defined as the date of the first dose of napabucasin. At 
least one cycle of study treatment is defined as at least 80% daily treatment compliance at 
targeted dose level during one cycle period prior to the first post-dosing imaging 
assessment. 
5.3. PK Analysis Set
The PK analysis set will include all patients who received at least one dose of napabucasin
and have at least one quantifiable concentration.


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5.4. Pharmacodynamics/Biomarker Analysis Set 
The Pharmacodynamics/Biomarker analysis population is defined as all patients that were 
treated and have at least one of the Pharmacodynamics/Biomarkers evaluated (including 
both the patients with only pre-treatment data and those with both pre- and/or 
post-treatment data).
6. DATA HANDLING
6.1. Methods for Handling Missing Dates 
All analyses and descriptive summaries will be based on the observed data. Except for the 
data otherwise specified in the language below, missing data will not be imputed or “carried 
forward”. For the patient data listings, no imputation of incomplete dates will be applied. 
The listings will present the incomplete dates without any change.
Missing or Partial Death Dates
x
If the entire date is missing, the death date will be imputed as the day after the date 
of last contact.
x
If the day or both day and month is missing, the death date will be imputed to the 
maximum of the full (non-imputed) day after the date of last contact and the 
following: 
o
If day is missing, day will be 1st of the month
o
If both day and month are missing, death month and day will be January 1st.
Date of Last Dose of All Study Drugs
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown 
or partially unknown, will be imputed as follows:
x
If the last date of study drug is completely missing and the End of Treatment eCRF 
page has not been completed and no death date has been entered, the patient should 
be considered ongoing and the cutoff date for the analysis should be used as the last 
dosing date.  
x
If the last date of study drug is completely or partially missing and there is EITHER 
a completed End of Treatment eCRF page OR a death date available (within the 
data cutoff date), then impute this date as the last dose date:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death 
date) 
= Last day of the month, if both Year and Month are available and Year = Year of 
min (EOT date, death date) and Month < Month of min (EOT date, death date)
= min (EOT date, death date), for all other cases.


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Missing Dates in Adverse Events/Concomitant Therapies
Dates missing the day or both the day and month of the year will adhere to the following 
conventions:
x
The missing day of onset of an AE or start date of a therapy will be set to:
-
the day of the first study treatment, if the onset yyyy-mm is the same as yyyy-
mm of the first study treatment
-
otherwise, first day of the month that the event occurred
x
The missing day of resolution of an AE or end date of a therapy will be set to:
-
the last day of the month of the occurrence. If the patient died in the same 
month, then set the imputed date as the death date
x
If the onset date of an AE or start date of a therapy is missing both the day and 
month, the onset date will be set to:
-
the date of the first treatment, if the onset year is the same as the year of the first 
study treatment
-
otherwise, January 1 of the year of onset
x
If the resolution date of an AE or end date of a therapy is missing both the day and 
month, the date will be set to:
-
December 31 of the year of occurrence. If the patient died in the same year, then 
set the imputed date as the death date
x
If date is completely missing, then no imputation will be done and the event will be 
considered as treatment emergent (for AEs) or concomitant (for medications) unless 
the end date rules out the possibility.
Missing Dates in Prior Therapies
Dates missing the day or both the day and month of the year will adhere to the following 
conventions:
x
The missing day of start or end date of prior therapy will be set to:
-
the 15th of the month or date of informed consent, whichever is earlier
x
If the start or end date of a prior therapy is missing both the day and month, the date 
will be set to: 
-
July 1 of the year or date of informed consent, whichever is earlier
x
If date is completely missing, then no imputation will be done 
Missing Efficacy Endpoints


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For primary and secondary efficacy analyses no values will be imputed for missing data. 
For time to event endpoints, non-event observations will be censored. For ORR/DCR, 
patients with no post-baseline tumor evaluations or missing baseline tumor evaluation 
will be counted as non-responders.  
Missing Age
Age will be computed from birth date to the date of Informed Consent, as (Date of 
Informed Consent – Date of Birth +1)/365.25 rounded down to the nearest integer. 
x
If birth date is missing day, day will be set to the 15th to minimize bias
x
If missing both month and day, birth date will be set to July 1 of the birth year
6.2. Definition of Baseline Values 
The baseline value is defined as the value collected at the time closest to, but prior to the 
start of study drug administration. CT and MRI scans may be considered for baseline 
assessment if they were performed within 30 days of the first scheduled dose of 
napabucasin.
6.3. Study Day 
Study day is calculated as:
x
Assessment date – first dose date + 1; if the assessment was performed on or after 
the first dose date.
x
Assessment date – first dose date; if the assessment was performed prior to the 
first dose date.
6.4. Visit Windows 
All data will be categorized based on the scheduled visit at which it was collected.  These 
visit designators are predefined values that appear as part of the visit tab in the eCRF. 
6.5. Dropouts 
Time to event parameters will be censored if patients drop out (withdraw from consent or 
lost to follow-up) before documentation of the events (progressive disease / death).  Rules 
for censoring for PFS are detailed in Appendix 1.2 Censoring for Time to Event Data
6.6. Pharmacokinetics
For individual concentration-time plots and the calculation of PK parameters using 
noncompartmental analysis, individual BLQ values will be converted using the following 
rules:
·         If a BLQ value occurs in a profile before the first quantifiable concentration, it will 
be assigned a value of zero.
·         If a BLQ value occurs after a quantifiable concentration in a profile and is


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immediately followed by a value above the LLQ, then the BLQ value should be treated as 
missing.
·         If a BLQ value occurs at the end of the collection interval (after the last 
quantifiable concentration) it will be treated as missing.
·         If two BLQ values occur in succession after Cmax, the profile will be deemed to 
have terminated at the first BLQ value and any subsequent quantifiable concentrations 
will be omitted from PK calculations by treating them as missing.
When imputing BLQ concentrations for the generation of summary statistics at a given 
time point, all BLQ values will be set to zero except when an individual BLQ falls 
between two quantifiable values, in which case it will be treated as missing. These same 
imputations apply to imputation of BLQ concentrations used for generation of 
concentration-time profiles based on summary statistics.
6.7. Pharmacodynamic Parameters 
Missing data for the pharmacodynamic parameters will be treated as such and no imputed 
values will be derived.
7. STATISTICAL METHODOLOGY AND STATISTICAL 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. Analysis for Time to Event Data 
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 intervals for each time-to-event endpoint (3) will be provided. The 6 month, 
1 year, and 18 month survival probability will be estimated using the Kaplan-Meier 
method and a 2-sided 95% CI will be calculated using the normal approximation to the 
log transformed cumulative hazard rate.
7.1.2. Analysis for Binary Data
Descriptive statistics (frequency and percentage) of binary endpoints for each treatment 
arm will be provided along with the corresponding 2-sided 95% confidence intervals using
the Exact Method based on the F distribution (Clopper-Pearson method) (2).
7.1.3. Analysis for Continuous Data
Descriptive statistics, such as the mean, standard deviation, median, minimum, and 
maximum values will be provided for continuous endpoints. Linear or non-linear models 
may be employed to analyze the continuous data. 


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7.2. Statistical Analyses  
7.2.1. Standard Analysis
Study Conduct and Patient Disposition
Patient disposition includes the number and percentage of patients for the following 
categories:  patients in each of the study populations, patients discontinued from the 
treatment, and patients ongoing.  All percentages will be based on the number of patients 
in the full analysis dataset (FAS) and will be summarized by arm, disease cohort, and dose 
level.
Demographic and Baseline Characteristics
Demographics will be summarized by arm, disease cohort, and dose level in a descriptive 
fashion in the FAS. Baseline demographic data to be evaluated will include age, sex, race, 
height, weight, smoking history, and other parameters as appropriate. 
BMI will be calculated as weight (kg) / [height (m)]2.
Age will be computed from birth date to the date of Informed Consent, as (Date of 
Informed Consent – Date of Birth +1)/365.25 rounded down to the nearest integer. 
Baseline disease characteristics will also be summarized by arm, disease cohort, and dose 
level. Since each disease cohort has specific disease characteristics pertaining to that 
cohort, each baseline disease characteristics table will vary dependent on the disease. 
Prior and Concomitant Medications
Prior and concomitant medications will be coded to ATC (Anatomical Therapeutic 
Chemical) classification and Drug Class using WHO Drug Dictionary (WHO-DD) March 
2015 and will be summarized by arm, disease cohort, and dose level.
Medications that start and stop prior to the date of first treatment administration 
(napabucasin or chemotherapy backbone, whichever is administered first) will be classified 
as ‘prior’ medications. If a medication starts on or after the date of first treatment 
administration up to the last dose date of study medication (inclusive), then the medication 
will be classified as ‘concomitant’. If a medication starts before the date of first treatment 
administration and stops on or after the date of first treatment administration, then the 
medication will be categorized as both a ‘prior’ and ‘concomitant’ medication.
Summaries of prior and concomitant medications will be provided by level 3 ATC 
classification and preferred name using frequencies and percentages for the FAS. A 
separate concomitant medications table using preferred base and level 4 ATC classification 
will also be provided using frequencies and percentages for the FAS.
Prior and Concomitant Treatment 


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Prior treatment will be summarized by arm, disease cohort, and dose level and listed for 
each patient in the FAS.
Prior cancer surgery will be summarized by the number and percentage of patients who 
underwent each type of prior cancer surgery. Procedures will be listed in alphabetical order.
The total dose of prior cancer radiotherapy will be summarized. 
Prior cancer therapies will be summarized by the number of unique agents per patients, the 
number and percentage of patients reporting each agent, time from start of first anticancer 
therapy to first dose date of napabucasin, and time from end of last anticancer therapy to 
first dose date of napabucasin. Prior cancer therapies will be coded to Agent Received using 
WHO Drug Dictionary (WHO-DD) March 2015. 
The reasons for all concomitant procedures will be summarized, and the procedures will 
be displayed alphabetically in the FAS.
Medical History
Medical history will be coded by SOC and PT using MedDRA 18.0.  Medical history will 
be summarized by SOC and PT using the number and percentage of patients for the FAS 
and will be summarized by arm, disease cohort, and dose level. 
Concurrent Medical Conditions
Concurrent medical conditions will be summarized by SOC and PT and maximum grade 
using the number and percentage of patients for the FAS and will be summarized by arm, 
disease cohort, and dose level.
Extent of Disease
All target lesions at baseline will be analyzed for the FAS. The number of target lesions,
the length of the largest target lesion, and sum of target lesions will be summarized by
arm, disease cohort, and dose level.
Extent of Exposure
Exposure will be summarized as dose received (cumulative dose and actual dose intensity) 
and as dose received relative to intended dose (relative dose intensity [RDI]).  
Cycle 1 dosing intensity will be summarized separately from Cycle 2 onwards for Arm C 
(CAPOX) and Arm F (Regorafenib) as capecitabine and regorafenib are permitted to have 
protocol-specified dose increases after cycle 1.
The information that will be summarized depends on how the study drug is dosed (e.g., 
infusion cyclical, oral daily, oral cyclical). All information regarding dosing will be 
obtained from the drug administration CRF.


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A FOLFOX6 regimen includes four agents: Oxaliplatin, leucovorin, 5-FU bolus, and 5-FU 
drip. A CAPOX regimen includes two agents: capecitabine and oxaliplatin. A FOLFIRI 
regimen includes four agents: Irinotecan, leucovorin, 5-FU bolus, and 5-FU drip. A 
regorafenib regimen consists of just regorafenib. The same applies for an irinotecan 
regimen.
Any regimen that also includes bevacizumab includes the agents needed for that regimen 
along with the single agent of bevacizumab.  
In what follows “time unit” can be e.g., weeks or days.
Actual treatment duration = actual end of treatment date – date of first dose of study drug 
+ 1, 
1.
For napabucasin, capecitabine in Arm C, and regorafenib in Arm F, the actual end 
of treatment date is the last dosing date
2.
For all other IV cyclic combination drugs in Arms A, B, C, D, E, and G, the actual 
end of treatment date = Last dosing date + interval - 1, where interval = 14 for Arms 
A, B, D, E, and G, and interval = 21 for oxaliplatin in Arm C (CAPOX). 
Note that the actual end of treatment date in this analysis is not the collected end of 
treatment date in the eCRFs. The actual end of treatment date in this analysis is being 
derived and may be different from what was recorded by sites.
Cumulative dose in a cycle or overall is the sum of the actual doses received in a cycle or 
overall, respectively.  
Actual Dose Intensity [DI]:
x
Overall actual DI (dose unit/week) = [overall cumulative dose] / [actual treatment 
duration in weeks].
Relative Dose Intensity (RDI): The basic intent is to evaluate dose per time unit factoring 
in dose reductions, interruptions, or delays.  
x
Relative dose intensity (RDI) overall
o
Intended DI (dose unit/time unit) = [intended cumulative dose per cycle] / 
[intended number of time units in a cycle]  
o
Overall RDI (%) = 100 × [overall actual DI] / [intended DI] 
Note:
x
The intended dose level is fixed at the start of treatment rather than the start of a 
cycle


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o
One exception is for capecitabine in Arm C and regorafenib in Arm F. For 
capecitabine, dose level is permitted to increase from 850 mg/m2 to 1000 
mg/m2 after cycle 1. For regorafenib, dose level is permitted to increase 
from 120 mg to 160 mg after cycle 1. So if dose level increases for
regorafenib between 20-35 days after first dose date, then updated
increased dose level is the new intended dose level for cycle 2 onwards. If 
dose level increases for capecitabine between 15-22 days after first dose 
date, then updated increased dose level is the new intended dose level for 
cycle 2 onwards.
o
Second exception is for all backbone therapies except for regorafenib. All 
other backbone therapies incorporate BSA or weight to calculate each dose.
Bevacizumab incorporates weight to calculate each dose—all other 
therapies incorporates BSA. Therefore, the BSA to be used for calculating 
each dose of the backbone therapies will be using the Mosteller method (see 
below) based on the last available weight and height prior to each infusion.
For bevacizumab, the last available weight prior to each infusion will be 
used for calculating each dose.
o
BSA [m2] = ((Height [cm] × Weight [kg])/3600) × 0.5
o
Calculated doses will be rounded to the nearest integer
o
Cumulative dose, actual dose intensity and relative dose intensity will 
remain missing if they cannot be derived due to missing weight, or BSA.
Height from the most recent earlier visit can be used if height is missing.
x
The intended cumulative dose of a combination drug per cycle is constant for all 
cycles
o
One exception is for capecitabine in Arm C and regorafenib in Arm F. If 
dose levels change as mentioned above within the specified window after 
first dose date, this updated intended dose level should be considered when 
calculating intended cumulative dose of this particular drug per cycle after 
cycle 1.
o
Second exception is for all backbone therapies except for regorafenib after 
the updated BSA or weight calculation prior to each infusion. The updated 
dose level based on changing BSA or weight should be considered when 
calculating intended cumulative dose of these drugs per cycle
x
The intended cumulative dose of napabucasin per cycle is calculated by (intended 
dose level per day) × (intended cycle duration in days)
o
Intended dose level per day for napabucasin should be obtained from dose 
cohort information
x
Dose unit of napabucasin and regorafenib is mg, dose unit of other combination 
drugs (except bevacizumab) is mg/m2, dose unit of bevacizumab is mg/kg
Treatment Compliance
Napabucasin compliance will be summarized by overall. 
1.
Overall: Treatment compliance for napabucasin is defined as follows:
(Cumulative actual total dose / total planned or intended dose) × 100 = % 


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compliance
2.
Daily treatment compliance will be reported for each patient for the following dose 
levels and intervals:
x
The % of days the patient received a total dose of at least 960 mg napabucasin out 
of actual treatment duration in days.   
x
The % of days the patient received a total dose of at least 480 mg napabucasin out 
of actual treatment duration in days.   
x
The % of days the patient received a non-zero dose of napabucasin out of actual 
treatment duration in days.
Daily treatment compliance will be grouped according to the following categories: <60%,
t 60% - < 80%, t 80% - < 90%, and t 90%, and will be summarized for all arms, disease 
cohorts, and dose levels.
These summaries will also be repeated for cycle 1 compliance.
Combination drugs compliance overall
1.
Overall: 
For any IV combination drug, compliance will be calculated using the following 
equation:
(Number of treatments administered / number of treatments that should have been 
administered) × 100 = % compliance
For any oral combination drug, compliance will be calculated using the following 
equation:
(Cumulative actual total dose / total planned or intended dose) × 100 = % 
compliance
7.2.2. Analysis for Primary Endpoint 
DLT (Phase Ib) 
Dose Limiting Toxicity (DLT) is the primary endpoint of the dose escalation component 
of the study.  A listing of the DLTs will be provided.
Objective Response Rate (ORR, Phase II) 
The objective response rate (ORR) is defined as the percentage of patients with a best 
overall response (BOR) of complete response (CR) or partial response (PR) based on 
RECIST 1.1. The categorizations of response (CR, PR, stable disease [SD], progressive 
disease [PD], and not evaluable [NE]) and the derivations of BOR is provided in Section 
8.1. The primary estimate of ORR will be based on the Response Analysis Set (RAS). 
ORR will be summarized for each treatment arm, disease cohort, and dose level along with 
the corresponding Exact 2-sided 95% CI using the Clopper Pearson method (2).


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7.2.3. Analyses for Secondary Endpoints 
Other Efficacy Endpoints Analysis 
The following secondary outcomes will also be assessed.
OS in the Full Analysis Set
OS in the FAS is defined as the time from first dose date of any study drug to death from 
any cause. Patients who are alive at the time of analysis or who have dropped out will be 
censored at their last date known to be alive. OS in months as calculated as (date of 
death/last known to be alive date – date of first dose of any study drug + 1) / 30.4375.
The survival of patients in all treatment groups, disease cohorts, and dose levels will be 
summarized by the Kaplan-Meier method and will be displayed graphically. The 95% CI
will be calculated based on the Brookmeyer and Crowley method [3]. The survival 
probability at 6 months, 1 year, and 18 months will also be summarized using the Kaplan-
Meier method and the 95% CI will be calculated using the normal approximation to the log 
transformed cumulative hazard rate. The OS summary for each arm within each disease 
cohort and dose level will only be provided when the number of events in that arm is at 
least 5.
PFS in the Full Analysis Set
PFS in the FAS is defined as the time from first dose of any study drug to the first objective 
documentation of disease progression or death due to any cause. If a patient has not 
progressed or died at the time of analysis, PFS will be censored on the date of the last tumor 
assessment. PFS in months is calculated as (first event date / censored date – date of first
dose of any study drug + 1) / 30.4375.
PFS will be reported as the median event time (and other quartiles) and the corresponding 
2-sided 95% CI for each treatment arm within each disease cohort and dose level. The 95% 
CI will be calculated based on the Brookmeyer and Crowley method. Estimates of the PFS 
curves obtained from the Kaplan-Meier method will be presented along with a graphical 
presentation of PFS curves. The survival probability at 6 months, 1 year, and 18 months 
will also be summarized using the Kaplan-Meier method and the 95% CI will be calculated 
using the normal approximation to the log transformed cumulative hazard rate. The PFS 
summary for each arm within each disease cohort and dose level will only be provided 
when the number of events in that arm is at least 5.
DCR in the Response Analysis Set
DCR is defined as the proportion of patients with a documented complete response, partial 
response, and stable disease (CR + PR + SD) based on RECIST 1.1. The primary estimate 
of DCR will be based on the Response Analysis Set (RAS). 
DCR will be summarized for each treatment arm within each disease cohort and dose level 
along with the corresponding Exact 2-sided 95% CI using the Clopper-Pearson method [2].


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PK Analysis 
Nuventra Pharma Sciences will compute PK parameters by noncompartmental analysis 
using Phoenix WinNonlin version 6.3 (Certara, L.P., Princeton, NJ), and generate results 
using a validated version of R version 3.4.0 or later (R Foundation for Statistical 
Computing, Vienna, Austria).
Demographics for patients included in the PK Analysis Set will be summarized in the PK 
report, summarized by napabucasin dose and concomitant treatment.
7.2.3.2.1. PK Concentrations 
Plasma concentrations will be listed and summarized by napabucasin dose, concomitant 
treatment, and nominal timepoint using descriptive statistics, including N, mean, standard 
deviation, coefficient of variation (CV), minimum, maximum, and median. Imputation of 
concentration data BLQ is described in Section 6.6.
Figures of individual and mean drug concentrations vs actual or nominal elapsed time will 
be presented on linear and semi logarithmic scales by day, napabucasin dose and 
concomitant treatment, as appropriate.
7.2.3.2.2. Pharmacokinetic Parameters  
Pharmacokinetic parameters, including maximum concentration at steady state 
(Cmax,ss), time of maximum concentration (Tmax), area under the plasma concentration 
time curve during a dosing interval at steady state (AUCtau), minimum concentration at 
steady state (Cmin,ss), total body clearance at steady state (CLss/F), volume of 
distribution during terminal elimination phase at steady state (Vz/F), and accumulation 
ratios for Cmax (Racc Cmax) and AUCtau (Racc AUCtau) will be listed and summarized 
by day, napabucasin dose, and concomitant treatment using descriptive statistics, 
including N, mean, SD, CV, geometric mean, geometric CV, minimum, maximum, and 
median. For Tmax, N, minimum, maximum, and median will be reported. 
All PK parameters will be estimated using actual elapsed time from dosing. Imputation of 
concentration data BLQ is described in Section 6.6.
Pharmacodynamic/Biomarker Analysis 
BBI is exploring several biomarkers in tumor tissues.  Tumor archival tissue and biopsies 
will be collected as described in the Laboratory Manual.  The correlations between the 
biomarker results, pharmacokinetic parameters, and measures of anti-tumor/anti-cancer
efficacy signals or safety signals will be explored if data allow and it is deemed appropriate. 


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7.2.4. Analyses for Other Endpoints 
All adverse events, laboratory parameters, vital signs, Karnosky performance status, 
physical examinations, and ECG data analyses will be summarized based on the FAS. 
These data will be summarized by arm, disease cohort, and dose level.
Adverse Events 
Overall Summary of AEs 
An AE will be regarded as treatment-emergent, if
x
it occurs for the first time on or after the first dose date of either napabucasin or
FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and 
without bevacizumab, or regorafenib or irinotecan up to 30 days after the last dose 
of study treatment; or
x
it occurs prior to the first dose date of either napabucasin or FOLFOX6 with and 
without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or 
regorafenib or irinotecan and worsens in severity on therapy or up to 30 days after 
the last dose of study treatment  
The date of the last dose of study treatment will be determined from either drug 
administration data or the end of study CRF, whichever date is later.
Adverse events will be coded by SOC and PT using the MedDRA® version 18.0. The 
severity of AEs will be graded by the investigator using NCI CTCAE Version 4.0. The
SOC, PT, and verbatim term will be included in the AE listings. 
An overview of treatment-emergent adverse events (TEAEs) will be provided.  The number 
and percentage of patients will be summarized for the following: 
1. Patients with at least one TEAE 
2. Patients with TEAEs of CTCAE grade 3 or higher
3. Patients with serious TEAEs
4. Patients with serious TEAEs related to napabucasin
5. Patients with serious TEAEs related to regorafenib
6. Patients with serious TEAEs related to backbone therapy
7. Patients with serious TEAEs related to study drug (napabucasin or FOLXFOX6 with 
and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or 
regorafenib, or irinotecan)
8. Patients with napabucasin-related TEAEs
9. Patients with napabucasin-related TEAEs of CTCAE grade 3 or higher
10. Patients with any study drug-related TEAEs
11. Patients with any study drug-related TEAEs of CTCAE grade 3 or higher


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12. Patients with regorafenib-related TEAEs
13. Patients with regorafenib-related TEAEs of CTCAE grade 3 or higher
14. Patients with backbone therapy-related TEAEs
15. Patients with backbone therapy-related TEAEs of CTCAE grade 3 or higher
16. Patients with TEAEs leading to any napabucasin dose modification
17. Patients with TEAEs leading to any napabucasin dose reduction
18. Patients with TEAEs leading to napabucasin dose stoppage
19. Patients with TEAEs leading to any oxaliplatin* dose modification
20. Patients with TEAEs leading to any oxaliplatin* dose reduction
21. Patients with TEAEs leading to any oxaliplatin* dose stoppage
*Repeated for leucovorin, 5-FU, irinotecan, regorafenib, capecitabine, and bevacizumab
Summary of TEAEs by System Organ Class and Preferred Term 
The number and percentage of patients with TEAEs by SOC and PT and maximum CTCAE 
grade will be summarized. A summary of TEAEs of CTCAE grade 3 or higher (Grade 3, 
4, 5) will be presented by SOC and PT and maximum CTCAE grade. A summary of 
TEAEs by PT and maximum CTCAE grade in descending order of frequency will be 
presented, and this same summary table will be repeated for TEAEs of at least grade 3. The 
most commonly reported TEAEs using different cutoffs (e.g., 2%, 5% or 10% or more of 
patients in either arm) will also be summarized by PT. TEAEs associated with dose 
reduction/dose stoppage of napabucasin will also be summarized by SOC and PT and 
maximum CTCAE grade.
The number and percentage of patients with TEAEs leading to end of treatment for 
napabucasin by SOC and PT and maximum CTCAE grade will be summarized. These 
TEAEs will be obtained from the End of Study CRF, as AEs leading to napabucasin 
treatment discontinuation were not collected in the AE CRF. 
Treatment-Related TEAEs
TEAEs reported with a relationship to a treatment or combination drug considered by the 
investigator to be ‘possible’, ‘probable’ or ‘definite’ will be considered “Related” to study 
treatment or combination drug, respectively. TEAEs reported with a relationship to a 
treatment considered by the investigator to be 'unlikely' or 'unrelated' will be considered as 
“Not Related” to study treatment. Missing relationships will be considered as “Related”.  
Similar summaries of all causality TEAEs will be provided.  
Serious TEAEs and Death
Treatment-emergent SAEs and treatment-related SAEs will be summarized by MedDRA 
SOC and PT and maximum CTCAE grade. 
Patients who experienced an SAE during the AE reporting period will be listed for all safety 
patients.  The number and percentage of patients who experience any treatment-emergent 


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SAE will be summarized by SOC, PT and maximum CTCAE grade. A similar summary 
for treatment-related TESAEs will be provided as well. 
Deaths that occur on or after the first dose of study treatment will be summarized. The 
number and percentage of patients who died during and after the study treatment will be 
presented, along with time to death from the last dose.  
TEAEs leading to death will also be summarized by MedDRA, SOC, PT, and maximum 
CTCAE grade.
A listing of death data will also be provided and will include all deaths that occurred during
the reporting period for deaths that started from the signing of the informed consent to the 
end of the follow-up period.  The listing will include date of death and the number of days 
relative to the administration of the first and last dose of study drug.
Adverse Events of Clinical Relevance
Selected AEs are specified for additional focus due to the potential clinical significance of 
these events and/or the potential association with the investigational product.  These events 
include those in the standard MedDRA query (SMQ) terms (narrow or broad, as noted): 
Table 2:  Adverse Events of Clinical Relevance SMQ Terms 
MedDRA v18.0 Term
SMQ class
Ventricular fibrillation
NA (individual PT)
Ventricular tachycardia
NA (individual PT)
Non-infectious diarrhea 
Broad
Gastrointestinal haemorrhage 
Narrow
Gastrointestinal obstruction 
Narrow
Acute kidney injury 
Narrow (acute renal failure)
Tables listing the incidence and maximum severity of these events in the full analysis set 
will be generated.
Laboratory Data 
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  If a lab value is reported using a non-numeric qualifier 
(eg, less than (<) a certain value, or greater than (>) a certain value), the given numeric 
value will be used in the summary statistics, ignoring the non-numeric qualifier. 
Baseline is defined as the last non-missing value prior to the date of first dose of any study 
drug. All records on or after first dose date (scheduled or unscheduled visit) will be 
considered as post-baseline. For all lab parameters collected in the CRF, summary statistics 
for baseline values and maximum change from baseline will be presented for each arm, 
disease cohort, and dose level based on the FAS. Figures of maximum post-baseline vs 
baseline values will be plotted for key lab parameters, including but not limited to ANC, 


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platelets, and liver function tests (ALT/SGPT, AST/SGOT, alkaline phosphatase, and total 
bilirubin) as well as E-DISH scatter plots.
The parameters to be analyzed are as follows:
x
Hematology:  hemoglobin, hematocrit, ANC, ALC, monocytes, eosinophils, 
basophils, platelets, red blood cell and white blood cell (WBC) count
x
Serum chemistry:  blood urea nitrogen, creatinine, total and direct bilirubin, LDH, 
albumin, alkaline phosphatase, AST, ALT, glucose, calcium, sodium, potassium, 
total protein, chloride, CO2 (bicarbonate), magnesium, and phosphorous
The results of laboratory parameters will be graded according to NCI CTCAE v4.0 and 
summarized at baseline and post baseline by maximum CTC grade. The CTCAE grading 
will be performed based on only observed values without considering any clinical 
symptoms or findings. Shift tables summarizing baseline grade to maximum CTCAE grade 
post baseline will be provided. The CTCAE terms to be graded are listed in Table 3.
 
Table 3:  CTCAE Grading for Laboratory Parameters 
Hematology
Biochemistry
White blood cell decreased
Creatinine increased
Leukocytosis
Blood bilirubin increased
Anemia
Alanine aminotransferase increased
Aspartate aminotransferase increased
Hemoglobin increased
Alkaline phosphatase increased
Platelet count decreased
Hypoalbuminemia
Neutrophil count decreased
Hyperkalemia
Lymphocyte count decreased
Hypokalemia
Lymphocyte count increased
Hypermagnesemia
Hypomagnesemia
Hypophosphatemia
Hyponatremia
Summary statistics will also be presented for shift from baseline urinalysis values.
x
Urinalysis: protein, glucose, and occult blood
Listings to be presented include hematology, serum chemistry, and urinalysis. These will 
include the test result, units, normal range (H and L), change from baseline, and CTCAE 
grades if graded.


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Electrocardiograms 
12-lead ECG with categorical results (Normal, Abnormal [Not clinically significant], 
Abnormal [clinically significant]) will be summarized at baseline and any time post 
baseline by treatment, disease cohort, and dose level. Shift tables showing results from 
baseline to worst post baseline will be provided. A patient listing will also be provided.
Physical Examination 
Physical examination abnormalities will be summarized for baseline and worst values any 
time post baseline by treatment group, disease cohort, and dose level.  Patients with 
clinically significant abnormal findings will be flagged in the data listing.
Karnofsky Performance Status 
Karnofsky Performance Status will be summarized in a shift table from baseline to worst 
post baseline for the FAS by treatment group, disease cohort, and dose level.
Vital Signs
Vital signs maximum change from baseline will be summarized by treatment group, 
disease cohort, and dose level.
Summaries of markedly abnormal vital signs parameters, including blood pressure (BP),
pulse, and BMI will be presented along with their study day by treatment group, disease 
cohort, and dose level. Values for vital signs for all patients will be presented in a listing. 
Markedly abnormal ranges for vital signs parameters are given in the table below.
Vital Sign Parameter
Markedly Abnormal 
(Low)
Markedly Abnormal 
(High)
Systolic BP
Absolute value ≤ 90 
mmHg, or a decrease from 
baseline ≥ 20 mmHg
Absolute value ≥ 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 ≥ 15 bpm
BMI
Absolute value ≤ 18 kg/m2
Absolute value ≥ 25 kg/m2


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8. REFERENCES  
1.
Protocol BBI608-246 A Phase Ib/II Clinical Study of BBI608 in Combination with 
Standard Chemotherapies in Adult Patients with Advanced Gastrointestinal Cancer, 
June 23rd, 2017
2.
Blyth C.R., Still H.A. [1983]. Binomial Confidence Intervals Journal of the American 
Statistical Association 78, 381.
3.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38:29-41, 1982.


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APPENDICES
8.1.  Appendix 1.1 Further Definition of Endpoints 
Table 4:  Response Criteria 
Evaluation of target lesions
Complete Response (CR):
Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis of 
<10 mm
Partial Response (PR):
At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline sum LD
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment 
started.  In addition to the increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  The appearance 
of one or more new lesions is also considered progression
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the 
treatment started
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size 
(<10 mm short axis)
Stable Disease (SD):
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above normal limits
Progressive Disease (PD):
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions
The best overall response (BOR) is the best response recorded from the start of the treatment 
until disease progression/recurrence and is determined as indicated in Table 5. BOR is derived 
from the sequence of overall response. Assessments done after PD or after “new anti-cancer” 
treatment but prior to PD will not be considered evaluation of best overall response. Tumor 
assessments will be performed every 8 weeks. BOR derivation (based on unconfirmed 
response) is derived from the sequence of overall response determined by the following order:
x
CR:  One objective status of CR documented before progression or start of new anti-
cancer therapy. 
x
PR:  One objective status of PR documented before progression or start of new anti-
cancer therapy, but not qualifying as CR.
x
SD:  At least 1 objective status of SD or better documented within at least 1 nominal 
scan interval (8 weeks – 5 days window = 51 days) after start date and before 
progression and the start of new anti-cancer therapy, but not qualifying as CR or PR.
x
PD:  Progression documented within 2 nominal scan intervals (or 16 weeks + 5 days 
window = 117) after start date and not qualifying as unconfirmed CR, unconfirmed 
PR, or SD.  


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x
NE:  All other cases.  Note that reasons for NE should be summarized and the following 
reasons could be used: 
•
Early death (Note: death prior to 8 weeks after start date)
•
No post-baseline assessments 
•
All post-baseline assessments have overall response NE
•
New anti-cancer therapy started before first post-baseline assessment
•
SD too early (<8 weeks after first dose but before first scheduled 
response assessment)
•
PD too late (>16 weeks after first dose date)
Special and rare cases where BOR is NE due to both early SD and late PD will be classified as 
‘SD too early’.
Table 5: Overall Response
Target lesions
Non-Target lesions
Evaluation of 
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not All Evaluated 
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Objective response rate (ORR) is defined as the proportion of patients with a documented 
complete response (CR) or partial response (PR) based on RECIST 1.1 as determined by the 
investigator assessment collected in the CRFs, relative to the Response Evaluable analysis set.


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Disease Control Rate (DCR) is the proportion of patients with a documented CR, PR, or SD 
based on RECIST 1.1 as determined by the investigator assessment collected in the CRFs, 
relative to the RAS.
A patient will be considered as a non-responder until proven otherwise.  Thus, the following 
patients are considered non-responders:
x
Do not have CR or PR while on study; or 
x
Do not have a baseline or post-baseline tumor evaluation; or 
x
Do not have an adequate baseline tumor evaluation; or 
x
Receive anti-tumor treatment other than the study medication prior to reaching a CR or 
PR; or 
x
Die, progress, or drop out for any reason prior to reaching a CR or PR. 
8.2. Appendix 1.2 Censoring for Time to Event Data 
Table 6 summarizes the censoring rules for the PFS analysis and displays censoring hierarchy 
for this study. Table 7 shows the general reasons for PFS censoring and where the censoring 
hierarchy in Table 6 came from.
Table 6:  Event or Censor Time for PFS and Censoring Hierarchy 
Censoring 
Hierarchy
Situation
Date of Event or Censor
Event / 
Censor
1
No baseline radiological tumor 
assessment available
Date of First Dose 
Censored
2
New anticancer treatment started 
before tumor progression or death
Date of previous adequate 
radiological assessment 
immediately prior to start of new 
therapy or Date of first dose, 
whichever comes later
Censored
3
Tumor progression (per 
RECIST 1.1) documented or death 
after 2 scan intervals following 
previous adequate radiological tumor 
assessment, no new anticancer 
treatment started
Date of previous adequate 
radiological assessment or Date of 
first dose, whichever comes later
Censored
4, 5
No tumor progression (per 
RECIST 1.1), no death reported and 
patient lost to follow-up or 
withdrawal of consent, no new 
anticancer treatment started
Date of last adequate radiological 
Assessment or Date of first dose, 
whichever comes later
Censored


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6
No tumor progression (per 
RECIST 1.1) and no death reported 
within 2 scan intervals following last 
adequate radiological tumor 
assessment or first dose date (if no 
post baseline tumor assessment 
available), no new anticancer 
treatment started
Date of last adequate radiological 
tumor assessment or Date of First 
Dose, whichever comes later 
Censored
7
No tumor progression (per 
RECIST 1.1) and no death reported 
and none of the conditions in the 
prior hierarchy are met
Date of last adequate radiological 
tumor assessment or Date of first 
dose, whichever comes later
Censored
No tumor progression (per 
RECIST 1.1) but death reported 
within 2 scan intervals following last 
adequate radiological
tumor assessment or first dose date 
(if no post baseline tumor assessment 
available)
Date of death
Event
Tumor progression (per 
RECIST 1.1) documented within 
2 scan intervals following previous 
adequate radiological tumor 
assessment
Earliest of the target, non-target 
and new tumor assessment dates
Event
Notes: (1) Symptomatic deteriorations (i.e. symptomatic progressions, which are not 
radiographically confirmed) will not be considered as progressions.
(2) If target, non-target and new lesion assessments have different dates within a visit, then the 
earliest of those dates will be considered as the date of the tumor assessment if the assessment 
for that visit is progressive disease (PD); otherwise the latest date will be used.
(3) Adequate radiographical tumor assessment refers to an assessment with overall response 
of CR, PR, SD or PD.
(4) Comparing date of last tumor assessment to date of first dose is necessary if the last tumor 
assessment is baseline assessment
Table 7:  PFS Censoring Reasons and Hierarchy 
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy before event. 
Start of new anti-cancer therapy
3
Event more than 16 weeks from last adequate post-baseline 
tumor assessment/start date
Event after missing assessments a


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4
No event and patient withdrawn consent 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and no adequate post-baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a more than 16 weeks after last adequate tumor assessment
For OS, patients last known to be alive are censored at date of last contact.
Date of Last Contact 
The date of last contact will be derived for patients not known to have died at the analysis data 
cutoff date using the latest complete date (non-imputed) among the following:
x
All patient assessment dates (e.g., blood draws [laboratory, PK], vital signs, 
performance status, ECG, tumor assessments, concomitant radiation, surgery)
x
Start and end dates of follow-up anti-cancer therapies 
x
AE start and end dates
x
Last date of contact where “Patient Remains in Follow-up” collected on the “Survival 
Follow-up” eCRF (do not use date of survival follow-up assessment unless status is 
alive)
x
Study drug start and end dates
x
Randomization date
x
Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).
Note: 
1.
This list is not all inclusive and should be agreed upon by the study team according to 
the data collected in the CRF
2.
Only dates associated with patient visits or actual examinations of the patient should 
be used. Dates associated with a technical operation unrelated to patient status (e.g., 
the date a blood sample was processed) should not be used. 
3.
Assessment dates after the cutoff date will not be applied to derive the last contact date.