Clinical trial NCT01776307
Conditions: Colorectal Cancer
Keywords: BBI608
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2012-03-01; Completion date: 2020-04-01
Enrollment: 200 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open label, multi-center, Phase 2 study of BBI608 in combination with cetuximab, panitumumab or capecitabine in patients with advanced colorectal cancer.

Detailed description:
This is an open label, multi-center, Phase 2 study of BBI608 administered in combination with either cetuximab, or panitumumab, or capecitabine. A cycle will consist of daily and continuous oral administration of BBI608 for four weeks in combination with either cetuximab, or panitumumab, or capecitabine.

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: BBI608 intervention 2: Panitumumab intervention 3: Capecitabine intervention 4: Cetuximab
Intervention descriptions: intervention 1: BBI608 is administered at 500 mg po bid continuously. intervention 2: Panitumumab will be administered IV on day 8 and 22 of each 28 day cycle at 6 mg/kg over 60 minutes. intervention 3: Capecitabine will be administered orally at 1000 mg/m2 bid daily on days 8-21 every three weeks. intervention 4: Cetuximab will be administered IV on day 5 at 400 mg/m2 intravenous infusion over 120 minutes as the initial dose, then weekly at 250mg/m2 over 60-minutes at subsequent cycles.

Protocol documents:
Prot_000.pdf: 
Confidential
Page: 1
TITLE:
A Phase II Clinical Study of BBI608 in Adult Patients
with Advanced Colorectal Cancer
PROTOCOL NUMBER:
BBI608-224
STUDY DRUG:
IND #:
BBI608
100,887
SPONSOR:
Boston Biomedical, 
Inc. 640 Memorial 
Drive
Cambridge, MA 02139
Telephone: (617) 674-6800
Fax: (617) 674-8662
MEDICAL MONITOR:
Matthew Hitron, MD
SAFETY FAX:
(617) 674-8662 (US)
SAFETY CONTACT:
(617) 674-6800 x8563
DATE OF PROTOCOL: 
DATE OF
AMENDMENT: 
September 22st, 2011
October 9th, 2014
2
Confidentiality Statement
The information contained in this document is confidential and the proprietary property of Boston Biomedical,
Inc. Any unauthorized use or disclosure of such information without the prior written authorization of Boston
Biomedical, Inc. is prohibited. 
Boston Biomedical, 
Inc. 640 Memorial 
Drive
Cambridge, MA 02139
Telephone: (617) 674-6800
Fax: (617) 674-8662
Matthew Hitron, MD
(617) 674-8662 (US)
(617) 674-6800 x8563


Confidential
Page: 2
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
SYNOPSIS
Study Title:
A Phase II Clinical Study of BBI608 in Adult Patients with
Advanced Colorectal Cancer
Study Number:
BBI608-224
Study Phase:
Phase II
Study Drug
BBI608, a novel investigational small molecule anticancer drug that targets
cancer stem cells.
Primary Objectives:
To determine the safety and preliminary anti-tumor activity of BBI608 when
administered 
in 
combination 
with 
Cetuximab, 
or 
Panitumumab, 
or
Capecitabine in adult patients with advanced colorectal cancer who have failed
first and second line treatment. 
The primary endpoint will be disease control rate, defined as the proportion of
patients with a documented complete response, partial response and stable
disease (CR + PR + SD) based on RECIST. The secondary endpoints will
include progression-free survival (PFS) and overall survival (OS).
Secondary
Objectives:
To  determine  the  pharmacokinetic  profile  of BBI608  and  Cetuximab,  or
Panitumumab, or Capecitabine when administered in combination. 
To determine the pharmacodynamics (biomarkers) of BBI608. 
To evaluate tolerability of two dosing regimens of BBI608 by comparing 
administration of BBI608 at 240 mg twice daily starting dose and escalating to 480 
mg twice daily after cycle 1 versus administration of BBI608 at 480 mg twice 
daily starting dose with dose adjustment permitted. 
To evaluate tolerability of BBI608 by comparing prophylactic administration of 
anti-diarrheal medication versus as needed administration of anti-diarrheal 
medication. The tolerability will be assessed using adverse event profile and 
achieved dose intensity.


Confidential
Page: 3
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Study Design:
This is an open label, multi-center, Phase II study of BBI608 administered in
combination with either Cetuximab, or Panitumumab, or Capecitabine. A
cycle will consist of daily and continuous oral administration of BBI608 for
four weeks in combination with either Cetuximab, or Panitumumab, or
Capecitabine.
Arm A (Cetuximab) - BBI608 is administered at 480 mg po twice daily
continuously and Cetuximab will be administered IV on day 5 at 400 mg/m2
intravenous infusion
over 120 minutes as  the initial dose, then weekly at
250mg/m2 over 60-minutes at subsequent cycles. 
Arm B (Panitumumab) - BBI608 is administered at 480 mg po twice daily
continuously and Panitumumab will be administered IV on day 8 and 22 of
each 28 day cycle at 6 mg/kg over 60 minutes. 
Arm C (Capecitabine) - BBI608 is administered at 480 mg po twice daily
continuously and Capecitabine will be administered orally at 1000 mg/m2 bid
daily on days 8-21 every three weeks. 
6 patients will be initially enrolled in each combination arm at a dose level of
480 mg twice daily (960 mg total daily dose) BBI608. If  1 out of 6 patients
have an observable DLT in the combination regimen, then that combination
arm may continue to accrue patients. If DLT occurs in  2 of the 6 patients in a
combination arm, then the combination arm will closed and no new patients
will be enrolled into this combination arm. A trial arm of BBI608 in
combination with Cetuximab, or Panitumumab, or Capecitabine will continue to 
enroll patients only if no more than 1 out of 6 patients for each combination has
an observable DLT. It is expected that approximately 60 to 80 CRC patients 
will be enrolled in the study.
Pharmacokinetics (PK) will be performed in the first cycle for the initial 6
patients of each combination arm of the study. 
Pharmacodynamic assessments will be performed in patients with accessible
tumors when tumor biopsy is possible.
Evaluation of anti-tumor activity of BBI608 in combination with Cetuximab, or
Panitumumab or Capecitabine will be performed at about 8 week intervals 
while patients remain on study. 
To evaluate the tolerability of BBI608, patients from each arm will be assigned to one 
of 4 sub-cohorts (with 6 patients in each sub-cohort IA, IB, IIA, IIB). The evaluation of 
tolerability will be done at select centers for the study arm that is continuing patient 
accrual and in which a total of 50 evaluable patients has not been reached. For each 
combination arm, patients assigned to sub-cohorts IA and IB will receive BBI608 at 
240 mg po twice daily (480 mg total daily dose) starting on day 1 of cycle 1. Intra-
patient dose escalation of BBI608 to 480 mg po twice daily (960 mg total daily dose) is 
allowed as tolerated. Patients assigned to sub-cohorts IIA and IIB will receive BBI608 
at 480 mg po twice daily (960 mg total daily dose) starting on day 1 of cycle 1. In case 
of toxicity, dose adjustment of BBI608 is permitted, as recommended in dose 
modification guidelines. Additionally, patients assigned to sub-cohorts IA and IIA will 
receive prophylactic anti-diarrheal treatment starting the day prior to day 1 of cycle 1. 
Patients assigned to sub-cohorts IB and IIB will anti-diarrheal treatment on an as 
needed basis starting with development of diarrhea above baseline. For each 
combination regimen, patients will be sequentially assigned to each of the 4 sub-
cohorts in the following order until 6 patients are accrued on each of the sub-cohorts: 
IA, IB, IIA, and IIB. If required, up to additional 20 patients may be assigned to 
selected sub-cohorts to validate the observations in initial 6 patients. 


Confidential
Page: 4
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Sub-
cohort
BBI608 Starting Dose Level 
Anti-diarrheal 
Administration
IA
240 mg bid (480 total daily dose)1
Prophylactic 
IB
240 mg bid (480 total daily dose)1
As needed
IIA
480 mg bid (960 total daily dose)2
Prophylactic 
IIB
480 mg bid (960 total daily dose)2
As needed
1Intra-patient dose escalation of BBI608 to 480 mg po twice daily (960 mg total 
daily dose) is allowed as tolerated..
2In case of toxicity, dose adjustment of BBI608 is permitted.
Study Population:
This study will enroll patients with advanced colorectal cancer. Patients 
must have received at least 2 lines of standard chemotherapy based on 
regimens containing 5-FU, irinotecan or oxaliplatin. Patients to be 
enrolled into the Cetuximab or Panitumumab combination arms must 
have colorectal cancer with wild-type K-Ras. 
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 at 480 mg twice daily (960 mg
total daily dose). In each cycle BBI608 will be taken daily for 4 weeks (28
days). BBI608 will be administered 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 Cetuximab, Cetuximab will be administered IV on day 5
at 400 mg/m2 intravenous infusion over 120 minutes as the initial dose, then
weekly at 250mg/m2 over 60-minutes at subsequent cycles. 
For patients receiving Panitumumab, Panitumumab will be administered IV on
days 8 and 22 of each 28 day cycle at 6 mg/kg over 60 minutes. 
For patients receiving Capecitabine therapy, Capecitabine will be administered
orally at 1000 mg/m2 bid daily on days 8-21 every three weeks.
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.


Confidential
Page: 5
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 Cetuximab, or
Panitumumab, or Capecitabine within 28 days of treatment: 
Ɣ CTCAE (Common Terminology Criteria for Adverse Events) Grade 4
hematological toxicity. 
Ɣ
Grade 3 or 4 non-hematological toxicity, except Grade 3 or 4
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. 
Ɣ 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. 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. 
Adverse events considered
related to Cetuximab, or Panitumumab
or
Capecitabine will not be considered DLTs for BBI608 in combination with
Cetuximab, or Panitumumab or Capecitabine.
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. Blood
samples for PK determination will be drawn on Days 5-12 and Days 26-33 for
the Cetuximab arm, on Days 8-15 and 22-29 for the Panitumumab arm, and on
Days 8-9 and Days 21-22 for the Capecitabine arm during the first cycle for the
first 6 patients in each combination arm. Response (increase or decrease) of
several biomarkers from biopsied tumors following BBI608 administration will
be examined in patients with accessible tumors for biopsy. Tumor biopsies
will be collected prior to the first dose of BBI608 and on day 8 of the first cycle
for patients with accessible tumors and who have signed the optional tumor
biopsy consent.


Confidential
Page: 6
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Statistical Methods:
In general, categorical variables will be summarized as the number and
percentage of patients in each category. Continuous variables will be
summarized by the mean, standard deviation, median, minimum, and
maximum.
The primary population for the efficacy evaluation will be the evaluable
population, defined as patients who have been treated with at least 80% of 1
complete cycle of BBI608 and a combination drug. The primary endpoint will
be disease control rate, defined as the proportion of patients with a documented
complete response, partial response and stable disease (CR + PR + SD) based
on RECIST. The secondary endpoints will include progression-free survival
(PFS) and overall survival (OS). PFS will be calculated from the date of
patient enrolment into the trial until documented disease progression based on
RECIST. OS will be calculated from the date of patient enrolment into the
trial until death. 
Patient sample size for each combination regimen is calculated based on a
power of 80 and a one-sided alpha of 5% to detect a disease control rate
improvement for Cetuximab and Panitumumab from about 30% (historical
DCR for 3rd and 4th line colorectal cancer) to 60% and for Capecitabine from
about 15% (historical DCR for 3rd line colorectal cancer) to 60%.
Safety analyses will include adverse events, SAEs, laboratory tests, and
physical examination changes from baseline. The safety population will
include all patients who have received any amount of BBI608 and the
combination drug. 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. 
Analysis and Sample size for sub-cohorts:
Each sub-cohort will be analyzed for number of days of Grade II/III diarrhea and 
% treatment compliance achieved during the first two cycles. The % treatment 
compliance will be calculated as the number of capsules actually ingested over 
the number of capsules that should have been ingested per dose level multiplied 
by 100. The research questions addressed by sub-cohorts are hypothesis-
generating and exploratory in nature. Initially 6 subjects will be assigned to each 
sub-cohort to assess the effect of intervention. Selected sub-cohorts will be 
extended to enroll up additional 20 patients. The decision of extending the 
enrollment will be based on clinical assessment without formal statistical 
testing. However, 20 patients will give 80% power to detect 20% difference in 
% treatment compliance between two arms and 57% power to detect the 
difference of 25% in the number of days of having Grade II/III diarrhea using 
two-sided Z test with pooled variance at type I error rate of 0.15. The control 
rates assumed are 70% for treatment compliance and 30% for diarrhea. The 
patients will be sequentially allocated to different sub-cohorts by the Sponsor 
to avoid section bias.


Confidential
Page: 7
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
TABLE OF CONTENTS
SYNOPSIS……………………………………………………………………………………..2
TABLE OF CONTENTS ...........................................................................................................5
1
PRECLINICAL SUMMARY AND STUDY RATIONALE .........................................11
1.1
Scientific Background of BBI608  .........................................................................11
1.2
Preclinical Efficacy ...............................................................................................11
1.3
GLP Toxicology ....................................................................................................11
1.4
Safety and Encouraging Signs of Antitumor Activity in Phase I ..........................12
2
STUDY OBJECTIVES ...................................................................................................13
2.1
Primary Objectives  ................................................................................................13
2.2
Secondary Objectives ............................................................................................13
3
SELECTION OF STUDY POPULATION  .....................................................................13
3.1
Inclusion Criteria ...................................................................................................13
3.2
Exclusion Criteria .................................................................................................14
3.3
Number of Patients ................................................................................................15
4
INVESTIGATIONAL PLAN .........................................................................................15
4.1
Overall Study Design  ............................................................................................15
4.2
Rationale for Study Design  ...................................................................................17
4.3
Selection of Dose ..................................................................................................17
4.4
Risk Benefit Assessment  .......................................................................................17
4.5
Dose-Limiting Toxicity ........................................................................................18
4.6
Study Duration  ......................................................................................................18
5
STUDY VISITS ..............................................................................................................18
5.1
Informed Consent  ..................................................................................................18
5.2
Pre-Study Evaluations (Baseline) (1 week ±3 days prior to the first dose of
BBI608*)  ...............................................................................................................18
5.3
On-Study Assessments  ..........................................................................................19
5.4
Tumor Evaluation Visits .......................................................................................23
5.5
End of Study Evaluation  .......................................................................................24
5.6
Discontinuation from Study ..................................................................................24
6
STUDY PROCEDURES ................................................................................................24
6.1
Medical History ....................................................................................................24
6.2
Physical Examination  ............................................................................................25
6.3
Clinical Laboratory Tests ......................................................................................25
6.4
Pharmacokinetic Assessments ..............................................................................25
6.5
Pharmacodynamic Assessments  ...........................................................................25
7
TREATMENT ................................................................................................................26
7.1
BBI608  ..................................................................................................................26
7.2
Dose Modifications  ...............................................................................................27
7.3
Treatment Compliance ..........................................................................................29
7.4
Blinding  .................................................................................................................29
7.5
Prior Treatment  .....................................................................................................29
7.6
Concomitant Medication  .......................................................................................29
8
SAFETY ASSESSMENTS  .............................................................................................31
8.1
Adverse Events  .....................................................................................................31
8.2
Serious Adverse Events  ........................................................................................32


Confidential
Page: 8
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
9
ASSESSMENT OF ANTI-TUMOR ACTIVITY IN SOLID TUMORS ........................32
9.1
Methods of Measurement .....................................................................................33
9.2
Baseline Documentation of “Target” and “Non-Target” Lesions  .........................33
9.3
Response Criteria ..................................................................................................34
9.4
Evaluation of Best Overall Response ....................................................................34
10
PLANNED STATISTICAL METHODS  ........................................................................34
10.1
General Considerations  .........................................................................................34
10.2
Determination of Sample Size ..............................................................................35
10.3
Analysis Populations  .............................................................................................35
10.4
Efficacy .................................................................................................................36
10.5
Demographics and Baseline Characteristics  .........................................................36
10.6
Statistical Analysis of Pharmacokinetic Variables  ...............................................36
10.7
Safety Analysis .....................................................................................................37
10.8
Analysis and Sample size for sub-cohorts……………………………………….42 
11
QUALITY CONTROL AND ASSURANCE .................................................................37
11.1
Compliance with the Protocol  ...............................................................................37
11.2
Registration and Enrollment  .................................................................................37
11.3
Removal, Replacement, or Early Withdrawals of Subjects ..................................37
12
COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL
CONSIDERATIONS AND INFORMED CONSENT  ...................................................37
12.1
Institutional Review Board  ...................................................................................38
12.2
Compliance with Good Clinical Practice and Ethical Considerations  ..................38
12.3
Informed Consent and Permission to Use Private Health Information  .................39
13
STUDY MANAGEMENT .............................................................................................39
13.1
Amendments to the Protocol  .................................................................................39
13.2
Investigator Brochure and Information Materials .................................................39
13.3
Pre-investigational Documents  .............................................................................40
13.4
Drug Inventory Record  .........................................................................................40
13.5
Disposition of Used and Unused Study Drug .......................................................40
13.6
Study Records  .......................................................................................................40
13.7
Record Retention  ..................................................................................................41
13.8
Subject Confidentiality .........................................................................................41
13.9
Monitoring ............................................................................................................41
13.10 Case Report Form (CRF) Completion  ..................................................................41
13.11 Final Site Report ...................................................................................................42
13.12 Final Study Report ................................................................................................42
13.13 Use of Information  ................................................................................................42
13.14 Publication  ............................................................................................................42
13.15 Research Outside the Terms of this Protocol  ........................................................43
14
APPENDIX A: SCHEDULE OF ASSESSMENTS  ......................................................44
15
APPENDIX C: PERFORMANCE STATUS  .................................................................47
16
APPENDIX D: PHARMACOKINETIC STUDIES ......................................................48
17
APPENDIX E: TUMOR BIOPSIES ...............................................................................54
18
APPENDIX F: CETUXIMAB, PANITUMUMAB AND CAPECITABINE PRODUCT
LABELS  ..........................................................................................................................56
19
SPONSOR SIGNATURE ...............................................................................................57
20
INVESTIGATOR’S SIGNATURE ................................................................................57


Confidential
Page: 9
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
21
REFERENCES  ................................................................................................................58


Confidential
Page: 10
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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
Cru
Complete response / unconfirmed
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


Confidential
Page: 11
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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
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
sCR 
Stringent complete response 


Confidential
Page: 12
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
SD 
Stable disease 
SE 
Standard error 
SGOT
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SPEP
Serum protein electrophoresis 
Tmax
Time to maximum plasma concentration 
TNM Scale 
Tumor node metastases scale 
ULN 
Upper limits of normal
UPEP
Urine protein electrophoresis
VGPR 
Very good partial response 
WBC 
White blood cell (count)


Confidential
Page: 13
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 a great promise for cancer patients (Lobo, Shimono et al. 2007 1; Boman and Wicha, 
2008 2; Please find a list of updated reviews on cancer stem cells in all major cancer types in the
special issue of Journal of Clinical Oncology on cancer stem cells (J Clin Oncol. 2008 Jun
10;26(17)). 3
BBI608 is the most advanced product candidate selected from our BBI6000 program designed by 
Boston Biomedical, Inc. (BBI) to target cancer stem cells. 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 CSCP3 pathway.
With our proprietary target discovery technology TPIV®, scientists at Boston Biomedical, Inc. have
discovered that the CSCP3 pathway activity is critical for self-renewal and survival of cancer stem 
cells in human cancer. Blocking the CSCP3 pathway 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), offering a wide therapeutic
window. The dependence on CSCP3 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. BBI608 monotherapy has demonstrated anti- 
metastatic activity using an in vivo spontaneous metastasis mouse models. These data suggest broad
potential of BBI608 for a wide variety of human 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 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.


Confidential
Page: 14
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 in 
recovery 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
mordibund 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 recovery 
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. 
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
A phase 1 dose escalation study (BBI608-101) in adult patients with advanced cancer was initiated to
determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and 
preliminary anti-tumor activity of BBI608. A modified Simon accelerated titration scheme was used
for dose escalation, with a cycle consisting of twice-daily oral administration of BBI608 for 4 weeks, 
and was repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or other
discontinuation criteria were met. 
The dose of BBI608 has been escalated from 20 mg to 2000 mg/day, and a MTD was not reached. 
Further dose escalation is limited by pill burden. Adverse events have been generally mild; the most 
common being grade 1-2 diarrhea and nausea. Grade 3 events included fatigue and transient diarrhea. 
BBI608 has exhibited favorable pharmacokinetics. The plasma concentration of BBI608 reached 
several folds above the IC50. Prolonged stable disease beyond 12 weeks was observed in about 60%
of evaluable patients, including patients with colon cancer, head and neck cancer, gastric cancer, 
ovarian cancer and breast cancer.  Complete regression of a metastatic lesion to the kidney was also 


Confidential
Page: 15
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
observed in one colon cancer patient.   Decrease in tumor markers (CEA and CA125) have been 
observed in colon cancer and ovarian cancer.
BBI608 has shown exciting signs of activity in colorectal cancer (CRC) patients in the phase I study 
where 22 CRC patients with k-Ras mutant or wild-type tumors have been enrolled. These patients
were all end-stage patients who had failed standard treatments for CRC including FOLFOX, 
FOLFIRI, Avastin, EGFR therapy (if k-Ras wild-type) and experimental drugs.  Thirteen (13)
patients were evaluable with 8 (62%) showing SD or MR (27.6% regression) yielding a disease 
control rate (DCR=CR+PR+SD) of 62% compared to the historical control of about 10% for similar 
CRC patients on best supportive care. Progression free survival (PFS) was 13 weeks compared to the
historical control of 7.7 weeks (hazard ratio = 0.382; 95% CI, 0.159 to 0.918; p=0.015) in CRC
patients on best supportive care.4,6
In addition, a phase Ib/II trial of BBI608 in combination with paclitaxel in patients with advanced
malignancies carried out under IND 100,887 has shown that BBI608 given at 500 mg bid (1000 mg
total daily dose) in combination with weekly paclitaxel is well tolerated.
In  summary,  BBI608  has  shown an excellent  safety  profile, favorable  pharmacokinetics,  and 
encouraging signs of antitumor activity. 
2
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives of the study are: 
• 
To assess the safety and preliminary anti-tumor activity of BBI608 in adult patients with
advanced colorectal cancer who have failed first and second line treatment, when BBI608 is
administered in combination with Cetuximab, or Panitumumab, or Capecitabine. The
primary endpoint will be disease control rate, defined as the proportion of patients with a
documented complete response, partial response and stable disease (CR + PR + SD) based on 
RECIST. The secondary endpoints will include progression-free survival (PFS) and overall
survival (OS). 
2.2
Secondary Objectives
The secondary objectives of the study are: 
• 
To determine the pharmacokinetic profile of BBI608 and Cetuximab, or Panitumumab, or 
Capecitabine when administered in combination.
• 
To determine the pharmacodynamics (biomarkers) of BBI608. 
• 
To evaluate tolerability of two dosing regimens of BBI608 by comparing administration of 
BBI608 at 240 mg twice daily starting dose and escalating to 480 mg twice daily after cycle 1 
versus administration of BBI608 at 480 mg twice daily starting dose with dose adjustment 
permitted. 
• 
To evaluate tolerability of BBI608 by comparing prophylactic administration of anti-diarrheal
medication versus as needed administration of anti-diarrheal medication. The tolerability will be 
assessed using adverse event profile and achieved dose intensity.
3
SELECTION OF STUDY POPULATION
This study will be conducted in patients with advanced metastatic colorectal cancer. 


Confidential
Page: 16
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
The study may be conducted at sites in Canada, the United States, 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 Harmonization (ICH), Good Clinical Practice (GCP), the local regulatory


Confidential
Page: 17
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
requirements, and permission to use private health information in accordance with the Health
Insurance Portability and Accountability Act (HIPPA) prior to study-specific screening 
procedures.
2.
A histologically or cytologically confirmed colorectal cancer that is metastatic, unresectable, 
or recurrent. 
3.
Patients must have received at least 2 regimens containing 5-FU, oxaliplatin, or irinotecan. 
4.
Patients to be enrolled in the Cetuximab or Panitumumab combination arms must have 
colorectal cancer which is K-Ras wild-type.
5.
 18 years of age.
6.
Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST
1.1, see Section 9).
7.
Karnofsky performance Status  70% (Section 15).
8.
Male or female patients of child-producing potential must agree to use contraception or
avoidance of pregnancy measures during the study and for 30 days after the last BBI608
dose.
9.
Females of childbearing potential must have a negative serum pregnancy test.
10. Aspartate transaminase (AST) and alanine transaminase (ALT) 2.5 × upper limit of normal
(ULN), or  3.5 × ULN with metastatic liver disease.
11. Hemoglobin (Hgb)  10 g/dl. 
12. Total bilirubin  1.5 × ULN.
13. Creatinine  1.5 × ULN or creatinine clearance > 60 mL/min/1.73 m2  for patients with
creatinine levels above institutional normal. 
14. Absolute neutrophil count  1.5 x 109/L. 
15. Platelets  100 x 109/L. 
16. Life expectancy  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 first dose provided all treatment-related adverse events have resolved or have been
deemed irreversible, with the exception for a single dose radiation up to 8 Gray (equal to 800 
RAD) with palliative intent for pain control up to 7 days before beginning the administration 
of BBI608. 
2.
Surgery within 4 weeks prior to first dose.
3.
Any known symptomatic brain metastases requiring steroids. Patients with treated brain
metastases must be stable for 4 weeks after completion of that treatment, with image
documentation required.  Patients must have no clinical symptoms from brain metastases and
must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol
enrollment. Patients with known leptomeningeal metastases are excluded, even if treated. 
4.
Pregnant or breastfeeding 


Confidential
Page: 18
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
5.
Significant gastrointestinal disorder(s), in the opinion of the Principal Investigator, (e.g., 
Crohn’s disease, ulcerative colitis, extensive gastric and small intestine resection) 
6.
Unable or unwilling to swallow BBI608 capsules daily. 
7.
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. 
3.3
Number of Patients
It is expected that approximately 60-80 patients will be enrolled in the study. Patient accrual will
occur over a period of time dependent upon the number of cohorts enrolled. 
4
INVESTIGATIONAL PLAN
4.1
Overall Study Design
This is an open-label, multicenter Phase II study of oral BBI608 administered with Cetuximab, or 
Panitumumab, or Capecitabine to patients with advanced metastatic colorectal cancer. The study is
based on a Simon 2-stage design that will examine the safety, tolerability and pharmacokinetics of
BBI608 and Cetuximab, or Panitumumab, or Capecitabine, and assess the preliminary anti-tumor 
activity of BBI608 when administered in combination with Cetuximab, or Panitumumab, or 
Capecitabine in patients with advanced colorectal cancer.
BBI608 treatment will be at a dose level of 480 mg twice daily (960 mg total daily dose). In each 
cycle, BBI608 will be taken daily continuously for 4 weeks (28 days). BBI608 will be administered 
twice daily approximately one hour prior to or two hours after meals with the first dose given in the 
morning and approximately 12 hours between doses.
For patients receiving Cetuximab therapy, Cetuximab will be administered IV on day 5 of cycle 1 at
400 mg/m2 intravenous infusion over 120 minutes as the initial dose, then weekly at 250mg/m2 over 
60-minutes at subsequent cycles.
For patients receiving Panitumumab therapy, Panitumumab will be administered IV on day 8, and 22 
of each 28 day cycle at 6 mg/kg over 60 minutes.
For patients receiving Capecitabine therapy, Capecitabine will be administered orally at 1000 mg/m2
bid daily on days 8-21 every three weeks.
Cycles will be repeated until progression of disease, unacceptable toxicity, or another discontinuation
criterion is met. In the case of toxicity, adjustment is permitted. If administration of Cetuximab, or 
Panitumumab, or Capecitabine is discontinued due to Cetuximab, or Panitumumab, or Capecitabine- 
related toxicity, administration of BBI608 will be continued until disease progression if tolerated.
Initially, 6 patients will be enrolled in each combination arm at a dose level of 480 mg twice daily 
(960 mg total daily dose) BBI608. If  1 out of 6 patients has an observable DLT  in  the combination
regimen, then that arm of the study will continue to enroll patients at 480 mg po twice daily (960 
mg total daily dose) of BBI608 following the Simon 2-stage design (see Table 1). If


Confidential
Page: 19
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
DLT occurs in  2 of the 6 patients in a combination arm, then that arm of the study will be closed
and no further patients will be enrolled. A given arm of the study of BBI608 in combination with 
Cetuximab, or Panitumumab, or Capecitabine will continue to enroll patients if no more than 1 out of
6 patients in the combination arm has an observable DLT. 
Number of Subjects with 
DLT at 480 mg bid BBI608
DLT Decision Rule
1 out of 6
Continue patient enrollment in combination arm
> 2 out of 6
Close combination arm of the study
The following number of colorectal cancer patients will be enrolled based on a two-stage Simon 
design with an alpha of 5% and a power of 80% to detect a disease control rate improvement for
Cetuximab and Panitumumab from about 30% (historical DCR for 3rd and 4th line colorectal cancer) 
to 60%, and a disease control rate improvement for Capecitabine from about 15% (historical DCR for
3rd line colorectal cancer) to 60%.
Table 1 Simon two-stage design for Phase II
Patient number
Combo Therapy
Stage 1
Stage 2
Total*
Cetuximab
8
16
24
Panitumumab
8
16
24
Capecitabine
6
12
18
*If any of the three arms reach a DCR of 60% or more at the end of Simon Stage 2, a one-time option 
to expand accrual to a total sample size of up to 50 patients may be implemented for each arm. 
Table 2 Disease Control Rate – Third Line
Monotherapy 
(Historical)
Combination * 
(Historical)
Combination with BBI608 
(Expected)
Cetuximab
30-40% 4,5
~ 63% 10-15
60% or more
Panitumumab
30-40% 6-8
~ 68% 16
60% or more
Capecitabine
~ 15% 9
~ 45% 17,18
60% or more
* 
Cetuximab + Irinotecan
Panitumumab + Irinotecan
Capecitabine + Mitomycin C 
For the Cetuximab and Panitumumab combination cohorts, if the disease control rate in stage 1
reaches 3 of  8 or above,  additional  patients will  be  enrolled into the stage 2 cohort. 
For  the


Confidential
Page: 20
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Capecitabine combination cohort, if the disease control rate in stage 1 reaches 2 of 6 or above, 
additional patients will be enrolled into the stage 2 cohort. 
To evaluate the tolerability of BBI608, patients from each arm will be assigned to one of 4 sub-
cohorts (with 6 patients in each sub-cohort IA, IB, IIA, IIB). The evaluation of tolerability will be 
done at select centers for the study arm that is continuing patient accrual and in which a total of 50 
evaluable patients has not been reached. For each combination arm, patients assigned to sub-cohorts 
IA and IB will receive BBI608 at 240 mg po twice daily (480 mg total daily dose) starting on day 1 of 
cycle 1. Intra-patient dose escalation of BBI608 to 480 mg po twice daily (960 mg total daily dose) is 
allowed as tolerated. Patients assigned to sub-cohorts IIA and IIB will receive BBI608 at 480 mg po 
twice daily (960 mg total daily dose) starting on day 1 of cycle 1. In case of toxicity, dose adjustment 
of BBI608 is permitted, as recommended in dose modification guidelines. Additionally, patients 
assigned to sub-cohorts IA and IIA will receive prophylactic anti-diarrheal treatment starting the day 
prior to day 1 of cycle 1. Patients assigned to sub-cohorts IB and IIB will anti-diarrheal treatment on 
an as needed basis starting with development of diarrhea above baseline. For each combination 
regimen, patients will be sequentially assigned to each of the 4 sub-cohorts in the following order 
until 6 patients are accrued on each of the sub-cohorts: IA, IB, IIA, and IIB. If required, up to 
additional 20 patients may be assigned to selected sub-cohorts to validate the observations in initial 6 
patients.  
Table 3 Tolerability Analysis of BBI608 
Sub-cohort
BBI608 Starting Dose Level 
Anti-diarrheal Administration
IA
240 mg bid (480 total daily dose)1
Prophylactic 
IB
240 mg bid (480 total daily dose)1
As needed
IIA
480 mg bid (960 total daily dose)2
Prophylactic 
IIB
480 mg bid (960 total daily dose)2
As needed
1Intra-patient dose escalation of BBI608 to 480 mg po twice daily (960 mg total daily dose) is allowed as 
tolerated. 
2In case of toxicity, dose adjustment of BBI608 is permitted.
4.2
Rationale for Study Design
Considerable data has been collected from the Phase I monotherapy study of BBI608 (Protocol 
BBI608-101) conducted in advanced oncology patients who have failed multiple previous regimens. 
Dose escalation for BBI608 has been successfully conducted from a total daily dose of 20 mg to 2000 
mg total daily dose. Further dose escalation is limited by pill burden. A MTD was not reached. In 
addition, a phase Ib/II trial of BBI608 in combination with paclitaxel in patients with advanced
malignancies carried out under IND 100,887 has shown that BBI608 given at 500 mg bid (1000 mg 
total daily dose) in combination with weekly paclitaxel is well tolerated.
Combination of cancer stem cell therapeutics with chemotherapy or a targeted agent would allow 
simultaneous inhibition of cancer stem cells as well as non-stem regular cancer cells.
Based on the activity seen in colorectal cancer patients in the phase I monotherapy trial, and the
excellent safety profile of BBI608, combination of BBI608 with Cetuximab, or Panitumumab or 
Capecitabine provides a good option for these patients.
4.3
Selection of Dose


Confidential
Page: 21
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
The dose escalation of BBI608 in the BBI608-101 Phase I study has reached a total daily dose of 
2000 mg without dose-limiting toxicity. No MTD was reached and further dose escalation above 
2000 mg total daily dose was limited by pill burden. Adverse events observed in the BBI608-101
phase I trial have been generally mild with the most common being: diarrhea, nausea, and fatigue. 
Grade 3 events include: fatigue or transient diarrhea. No bone marrow suppression or neuropathy 
was observed.
In the BBI608-224 study, administration of BBI608 will be begin at a dose of 480 mg twice daily 
with a total daily dose of 960 mg, in combination with Cetuximab, or Panitumumab, or Capecitabine
with exception of patients enrolled into the IA and IB combination arm sub-cohorts, for whom 
administration of BBI608 will begin at a dose of 240 mg twice daily with a total daily dose of 480 mg 
in cycle 1. Intra-patient dose escalation of BBI608 to 480 mg po twice daily (960 mg total daily dose) 
is allowed as tolerated.
.
4.4
Risk Benefit Assessment
Cancer stem cell inhibitors offer an exciting approach to the treatment of advanced malignancies. 
Preclinical studies of BBI608 indicate that the drug is active against a wide range of solid tumors. 
Encouraging signs of antitumor activity have been observed in the BBI608-101 phase I trial. 
Combination of cancer stem cell therapeutics with chemotherapy or targeted agents would allow 
enhanced simultaneous inhibition of cancer stem cells as well as non-stem regular cancer cells.
BBI608 has been well tolerated in phase I trials. A MTD was not reached in the BBI608-101 Phase I
study with doses escalated from 20 mg up to 1000 mg bid (2000 mg total daily dose). Further dose
escalation above 2000 mg/day was limited by pill burden. 
Adverse events observed in the BBI608-101 phase I trial have been generally mild with the most 
common being: diarrhea, nausea, and fatigue. Grade 3 events include: fatigue or transient diarrhea. 
There is no clinically significant overlap between adverse events observed for BBI608 and the 
adverse effects of Cetuximab, Panitumumab, or Capecitabine.
The sponsor believes that the proposed study is acceptable in the context of its risks and benefits.


Confidential
Page: 22
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 in combination with Cetuximab, or Panitumumab or Capecitabine within 
28 days of treatment. DLT will be scored during the 28 days of BBI608 treatment. 
• 
Grade 4 hematological toxicity
• 
Grade 3 or 4 non-hematological toxicity, except: 
o
Grade 3 or 4 nausea/vomiting/anorexia, diarrhea and fatigue will be considered a
DLT only if it persists more than three (3) days despite optimal medical management 
o
Alopecia will not be considered a DLT 
Adverse events considered related to Cetuximab, or Panitumumab or Capecitabine will not be
considered DLTs.
4.6
Study Duration
Patients will receive treatment with BBI608 and Cetuximab, or Panitumumab, or Capecitabine until 
progression of disease, unacceptable toxicity or another of the discontinuation criteria is documented 
(see Section 5.6). It is expected that most patients will receive between one and four cycles of
BBI608 and Cetuximab, or Panitumumab, or Capecitabine for a treatment period of 4 to 16 weeks.
5
STUDY VISITS
Study Visits will consist of a Pre-Study Evaluation, during which the patient is evaluated to determine 
suitability for entry into the study, Cycle 1 Evaluations which will be performed on Weeks 1, 2, 3 and 
4 of the first cycle only for Cetuximab, on Weeks 2 and 4 the first cycle only for Panitumumab, and 
on Weeks 2 and 3 the first cycle only for Capecitabine, evaluations in Cycle 2 and beyond, which will 
be performed in Week 1 or 2 of each cycle, and an End-of-Study Evaluation. (See Section 14 for a
schedule of Assessments) 
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 
entered into the study. 
5.1
Informed Consent
Patients who agree to participate will sign the approved informed consent and will be provided a copy 
of the signed document. 
5.2
Pre-Study Evaluations (Baseline) (1 week ±3 days prior to the first dose of BBI608*)
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


Confidential
Page: 23
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
• 
Karnofsky performance status (see Section 15) 
• 
Vital signs (weight, temperature, blood pressure, height, respiration and pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Serum pregnancy test (if applicable)
• 
Tumor markers if applicable 
• 
Tumor biopsy, if applicable (see Section 6.5.1) 
• 
12-lead electrocardiogram (ECG) 
• 
Tumor measurement and staging[computed tomography (CT) or magnetic resonance imaging 
(MRI) acceptable] * 
*All CT and MRI scans can be used as the baseline assessment if they were performed within
three weeks prior to the first scheduled dose of BBI608.
Archival tissue samples from a prior biopsy or surgery should be collected from all patients enrolled
in the clinical trial if they are available (See Section 17: Appendix E).
5.3
On-Study Assessments
5.3.1
Cetuximab Arm
5.3.1.1 Week 1 (Cycle 1, Day 1) 
• 
Dispense BBI608 (four day supply) 
• 
12-lead electrocardiogram (2 hours after first BBI608 dose)
5.3.1.2 Week 1 (Cycle 1, Day 5) 
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Assess AEs 
• 
Record concomitant medication
• 
Cetuximab, IV infusion starting about 3 hours after morning dose of BBI608 
• 
The second dose of BBI608 will be given approximately 12 hours after the first dose.
• 
Blood samples for pharmacokinetics, (for only the first 6 patients enrolled in this arm).
• 
Dispense BBI608 (one week supply) 
Blood samples for pharmacokinetics will be collected immediately prior to the first dose of BBI608 
and will continue through 171 hours after administration of the first dose of BBI608. Specific details
for the collection of blood samples for pharmacokinetics can be located in Sections 6.4 and Section 
16.


Confidential
Page: 24
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
5.3.1.3 Week 2 (Cycle 1, Day 8) 
• 
Tumor biopsy, if applicable (see Section 6.5.1) 
5.3.1.4 Week 2 (Cycle 1, Day 12) 
The following assessments will be made during this visit: 
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Assess AEs 
• 
Record concomitant medication
• 
Cetuximab IV infusion, starting at about 3 hours after morning dose of BBI608 Dispense 
BBI608 (one week supply) 
5.3.1.5 Week 3 (Cycle 1, Day 19) 
The following assessments will be made during this visit: 
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Assess AEs 
• 
Record concomitant medication
• 
Cetuximab IV infusion, starting at about 3 hours after morning dose of BBI608 
• 
Dispense BBI608 (one week supply) 
5.3.1.6 Week 4 (Cycle 1, Day 26) 
The following assessments will be made during this visit: 
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Assess AEs 
• 
Record concomitant medication
• 
Cetuximab IV infusion, starting at about 3 hours after morning dose of BBI608 
• 
Blood samples for pharmacokinetics, (for only the first six patients enrolled in this arm.) 
• 
The second dose of BBI608 will be given about approximately 12 hours after the first dose.
• 
Dispense BBI608 (one week supply) 


Confidential
Page: 25
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Blood samples for pharmacokinetics will be collected immediately prior to the first dose of BBI608 
and will continue through 171 hours after administration of the first dose of BBI608. Specific details
for the collection of blood samples for pharmacokinetics can be located in Sections 6.4 and Section 
16.
5.3.2
Panitumumab Arm
5.3.2.1 Week 1 (Cycle 1, Day 1) 
• 
Dispense BBI608 (1 week supply) 
• 
12-lead electrocardiogram (2 hours after first BBI608 dose)
5.3.2.2 Week 2 (Cycle 1, Day 8) 
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Assess AEs 
• 
Tumor biopsy, if applicable (see Section 6.5.1) 
• 
Record concomitant medication
• 
Panitumumab, IV infusion starting about 3 hours after morning dose of BBI608 
• 
The second dose of BBI608 will be given approximately 12 hours after the first dose.
• 
Blood samples for pharmacokinetics, (for only the first six patients enrolled in this arm.) 
• 
Dispense BBI608 (two week supply) 
Blood samples for pharmacokinetics will be collected immediately prior to the first dose of BBI608 
and will continue through 171 hours after administration of the first dose of BBI608. Specific details
for the collection of blood samples for pharmacokinetics can be located in Sections 6.4 and Section 
16.
5.3.2.3 Week 4 (Cycle 1, Day 22) 
The following assessments will be made during this visit:
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Assess AEs 
• 
Record concomitant medication
• 
Panitumumab IV infusion, starting at about 3 hours after morning dose of BBI608 
• 
The second dose of BBI608 will be given approximately 12 hours after the first dose.


Confidential
Page: 26
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
• 
Blood samples for pharmacokinetics, (for only the first six patients enrolled in this arm.) 
• 
Dispense BBI608 (two week supply) 
Blood samples for pharmacokinetics will be collected immediately prior to the first dose of BBI608 
and will continue through 171 hours after administration of the first dose of BBI608. Specific details
for the collection of blood samples for pharmacokinetics can be located in Sections 6.4 and Section 
16.
5.3.3
Capecitabine Arm
5.3.3.1 Week 1 (Cycle 1, Day 1) 
• 
Dispense BBI608 (one week supply) 
• 
12-lead electrocardiogram (2 hours after first BBI608 dose)
5.3.3.2 Week 2 (Cycle 1, Day 8) 
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Assess AEs 
• 
Tumor biopsy, if applicable (see Section 6.5.1) 
• 
Record concomitant medication
• 
The second dose of BBI608 will be given approximately 12 hours after the first dose.
• 
Blood samples for pharmacokinetics, (for only the first six patients enrolled in this arm.) 
• 
Dispense BBI608 (one week supply) 
• 
Dispense Capecitabine (two week supply) 
Blood samples for pharmacokinetics will be collected immediately prior to the first dose of BBI608 
and will continue through 24 hours after administration of the first dose of BBI608. Specific details
for the collection of blood samples for pharmacokinetics can be located in Sections 6.4 and Section
16.
5.3.3.3 Week 3 (Cycle 1, Day 15) 
The following assessments will be made during this visit: 
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Assess AEs 
• 
Record concomitant medication


Confidential
Page: 27
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
• 
Dispense BBI608 (1 week supply) 
5.3.3.4 Week 4 (Cycle 1, Day 21) 
The following assessments will be made during this visit: 
• 
Karnofsky performance status 
• 
Vital signs (weight, pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Assess AEs 
• 
Record concomitant medication
• 
The second dose of BBI608 will be given approximately 12 hours after the first dose.
• 
Blood samples for pharmacokinetics, (for only the first six patients enrolled in this arm.) 
• 
Dispense BBI608 (1 week supply) 
Blood samples for pharmacokinetics will be collected immediately prior to the first dose of BBI608 
and will continue through 24 hours after administration of the first dose of BBI608. Specific details
for the collection of blood samples for pharmacokinetics can be located in Sections 6.4 and Section
16.
5.3.3.5 Monthly Evaluations (Cycle 2 and beyond, all arms)
5.3.3.6 Week 1 or 2 (Day 1 – Capecitabine: Day 5 – Cetuximab;  Day 8 - Panitumumab) 
Patients will have the following assessments:
• 
Physical examination
• 
Karnofsky performance status 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Tumor markers, if applicable 
• 
Assess adverse events (AE) 
• 
Record concomitant medication
• 
Cetuximab or Panitumumab IV infusion starting about 3 hours after morning dose of BBI608 
(for Cetuximab and Panitumumab arms respectively) 
• 
Dispense BBI608 (28 day supply) 
• 
Dispense Capecitabine (sufficient for Cycle) 
5.4
Tumor Evaluation Visits
Disease status and tumor response will be assessed in eight-week intervals up to one year after 
starting  therapy (calculated  from  the  first  dose  of  BBI608)  or  as  clinically indicated.  Standard


Confidential
Page: 28
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
imaging studies should be performed according to institutional procedures. Tumor response for solid
tumors will be evaluated using the guidelines for Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) outlined in Section 9.
Once progression of disease during therapy is documented, patients must be taken off treatment and
may receive any therapy as determined by their treating physician.
5.5
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.
The following assessments will be made during the end of study visit: 
• 
Physical examination
• 
Karnofsky performance status 
• 
Vital signs  (weight, temperature, blood pressure, respiration and pulse)
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Liver function tests (see Section 6.3) 
• 
Electrolytes (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
12-lead ECG 
• 
Tumor marker, if applicable 
• 
Tumor biopsy, if applicable (see Section 6.5.1) 
• 
Tumor measurement and staging 
• 
Assess adverse events 
• 
Record concomitant medications
5.6
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 
• 
Lost to Follow-up 
• 
Death 
• 
Clinically unacceptable toxicities despite optimal treatment.
6
STUDY PROCEDURES
6.1
Medical History
Medical history will include but not limited to the following: 


Confidential
Page: 29
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
• 
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, 
previous chemotherapy, including dates and duration of treatment, level of response per 
RECIST and duration of response, previous radiation therapy, including anatomic site, dose
and date of treatment
• 
Other patient characteristics will be summarized as appropriate 
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 (Section 15).
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, hematocrit, white blood cell count with 5-part 
differential, red blood cell, platelet. 
• 
Blood chemistry: HCO2, calcium, phosphorus, magnesium, albumin, glucose, and serum 
creatinine 
• 
Liver function tests: AST, ALT, lactate dehydrogenase (LDH), alkaline phosphatase, total
and direct bilirubin, uric acid, total protein and blood urea nitrogen (BUN) 
• 
Electrolytes: sodium, potassium, and chloride 
• 
Routine urinalysis: dipstick and microscopy including protein, specific gravity, glucose and 
blood
• 
Serum pregnancy test for female patients of childbearing potential. 
6.4
Pharmacokinetic Assessments
Blood samples for the PK of BBI608 and Cetuximab, or Panitumumab, or Capecitabine will be
collected from the first 6 patients enrolled in each combination arm. Approximately 30 blood 
samples for PK will be collected for each patient. Collection, storage, and shipping of PK samples
will be performed as described in Appendix D. 
6.5
Pharmacodynamic Assessments
Pre-clinical studies conducted 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 provided the patient has accessible tumor and has signed the optional tumor biopsy consent. 
The goal of the proposed biomarker study is to examine the response of biomarkers in patients treated 
with BBI608. For tumor biopsies, tumor samples will be obtained before and after dosing in selected
subjects. Subject tumor samples will be processed for determination of pharmacodynamic markers of 
in malignant tissue by histopathology and flow cytometry. 


Confidential
Page: 30
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
6.5.1    Tumor Biopsy 
Patients who are identified by the Principal Investigator as having a lesion, which could be biopsied 
with a minimally invasive procedure, will be asked to sign an additional consent. Tumor samples
should be collected at baseline and at 4 h after administration of the BBI608 morning dose on Day 8. 
Collection, storage, and shipping of tissue samples will be performed as described in Appendix E. 
7
TREATMENT
7.1
BBI608
BBI608 capsules will be supplied to the pharmacy at the clinical sites. BBI608 will be labeled as an 
investigational agent, limited by federal law. The pharmacist will dispense an appropriate number of
each strength capsule to the Principal Investigator for in-clinic dosing. The appropriate quantity of 
capsules will be dispensed to the patient depending on the combination regimen.
For the Cetuximab arm, the appropriate number of capsules will be dispensed for four days of daily
dosing on day 1, 1 week of daily dosing on day 5, day 12, day 19, and day 26 during cycle 1, and for
1 month of daily dosing for cycle 2 and beyond at the prescribed dose, including two extra doses.
For the Panitumumab arm, the appropriate number of capsules will be dispensed for eight days of 
daily dosing on day 1, 2 weeks of daily dosing on day 8, and 2 weeks of daily dosing on day 21
during cycle 1, and for 1 month of daily dosing for cycle 2 and beyond at the prescribed dose, 
including two extra doses.
For the Capecitabine arm, the appropriate number of capsules will be dispensed for 1 week of daily 
dosing on day 1, 1 week of daily dosing on day 8, 1 week of daily dosing on day 15, 2 weeks of daily
dosing on day 21, and for 1 month of daily dosing for cycle 2 and beyond at the prescribed dose, 
including two extra doses. These instructions must appear on the label for the container in which 
capsules are delivered to the patient. 
Cetuximab, Panitumumab, and Capecitabine will be handled as described in the Product Labels
approved by US FDA or Health Canada (see Appendix F).
7.1.1
Investigational Product Accountability 
BBI will provide all BBI608 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 study drug will be stored at room temperature, in a secure locked 
area, accessible to authorized personnel only. 
Accurate records of all BBI608 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 daily for 28 consecutive days. BBI608 will be administered 
twice daily, approximately one hour prior to or two hours after meals, with the first dose 
given in the morning. 


Confidential
Page: 31
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
7.1.3
Cetuximab, Panitumumab, or Capecitabine Administration
• 
Detailed instructions for the preparation, premedication, and administration of Cetuximab, 
Panitumumab, or Capecitabine are provided in the Product Labels approved by Health 
Canada or US FDA.
• 
Cetuximab will be administered via IV on Days 5, 12, 19 and 26 of a 28 day cycle, about 3 
hours after the first daily dose of BBI608. Panitumumab will be administered via IV on Days
8, and 22 of a 28 day cycle, about 3 hours after the first daily dose of BBI608. Capecitabine
will be administered orally twice-daily for two weeks out of three weeks. The first dose of 
Capecitabine should be taken about 3 hours after the first daily dose of BBI608 on day 8 of 
each 3 week cycle of Capecitabine.
7.1.4
Diarrhea Management
For each combination arm, treatment for BBI608-related diarrhea will be instituted on a prophylactic or 
on an as needed basis depending on sub-cohort assignment.
Patients assigned to sub-cohorts IA and IIA will receive prophylactic anti-diarrheal medication starting 
the day prior to day 1 of cycle 1. With development of intolerable grade 2 diarrhea or greater, 
prophylactic anti-diarrheal regiment may be adjusted as needed. Patients assigned to sub-cohorts IB and 
IIB will receive anti-diarrheal medication on an as needed basis starting with development of BBI608-
related intolerable grade 2 or above diarrhea. Patients in all 4 sub-cohorts who develop sub-optimal 
diarrhea control while on protocol therapy will have adjustment of their anti-diarrheal regiment as 
needed. 
The following treatments are suggested for diarrhea and accompanying abdominal cramping 
management:
Diarrhea & Abdominal Cramping Management 
Diphenoxylate/atropine (Lomotil) 5 mg QID until control (max 20 mg/day); then maintain at 5 mg BID
Loperamide (Imodium/Gastrostop) 4mg followed by 2 mg Q 4 hours or after each unformed stool (max 16 
mg/day); then maintain at 2-4 mg BID
Systemic opioids (e.g. hydromorphone [Dilaudid], codeine) have been found effective in reducing abdominal pain 
and diarrhea
Hyoscine butyl (Buscopan), or hyoscyamine (Levsin) can also be used for abdominal cramps
7.1.5
Body Surface Area Calculation
The calculation of the dose of Cetuximab or Panitumumab will be based on the patient’s body surface 
area (BSA). The BSA will be calculated before each cycle, based on the actual height and weight of 
the patient. The calculated dose will be adjusted downward to the nearest whole milligram. 
7.2
Dose Modifications
7.2.1
Cetuximab
Infusion Reactions:  Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI


Confidential
Page: 32
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
CTC Grades 3–4 infusion reactions.
Immediately and permanently discontinue Cetuximab for severe (grade 3 or 4) infusion reactions 
requiring medical intervention and/or hospitalization.
Dermatological toxicity:  If a patient experiences severe acneiform rash (grade 3 or 4), Cetuximab 
treatment adjustment should be made according to Table 3.
Table 3. Cetuximab Dose Modification Guidelines for Rash
Severe
Acneiform Rash
Cetuximab
Outcome
Cetuximab Dose
Modification
1st occurrence
Delay infusion 1 to 2
weeks
Improvement
Continue at 250 mg/m2
No improvement
Discontinue Cetuximab
2nd occurrence
Delay infusion 1 to 2
weeks
Improvement
Continue at 200 mg/m2
No improvement
Discontinue Cetuximab
3rd occurrence
Delay infusion 1 to 2
weeks
Improvement
Continue at 150 mg/m2
No improvement
Discontinue Cetuximab
4th occurrence
Discontinue Cetuximab


Confidential
Page: 33
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
7.2.2
Panitumumab 
Infusion Reactions: Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI
CTC Grades 3–4 infusion reactions.
Immediately and permanently discontinue Panitumumab for severe (grade 3 or 4) infusion reactions 
requiring medical intervention and/or hospitalization.
Dermatological  toxicity: 
If a patient experiences dermatological toxicities (grade 3 or 4), 
Panitumumab treatment should be withheld until the toxicities have improved ( grade 2). Once
improved, reinstate Panitumumab administration at 50% of the original dose. If toxicities do not
worsen, escalate each additional dose of Panitumumab by 25% increments of the original dose until
the recommended starting dose is reached. If toxicity dose not resolve to at least grade 2 after 
withholding 1 or 2 doses of Panitumumab, or if toxicity worsens or becomes intolerable at 50% of the 
original dose level, the use of Panitumumab should be permanently discontinued. 
7.2.3
Capecitabine 
Hematological: 
ANC
(x10
9/L)
Platelets
(x10
9/L)
1st Event Dose
2nd Event Dose
3rd Event Dose
4th Event Dose
 1.5
and
 75
100%
100%
100%
100%
1-1.49
or
50-74.9
delay* then 100%
delay* then 75%
delay* then 50%
discontinue
0.5 - 099
or
25 - 49.9
delay* then 75%
delay* then 50%
discontinue
discontinue
< 0.5
or
< 25
discontinue or
delay* then 50%
discontinue
discontinue
discontinue
* delay until ANC  1.5x10
9/L and platelets  75 x10
9/L
Hand-Foot Reaction
Grade
1st Event Dose
2nd Event Dose
3rd Event Dose
4th Event Dose
1
100%
100%
100%
100%
2
delay* then 100%
delay* then 75%
delay* then 50%
discontinue
3
delay* then 75%
delay* then 50%
discontinue
discontinue
* delay until until resolved to grade 0-1 
Other Non-Hematological Toxicity
Grade
1st Event Dose
2nd Event Dose
3rd Event Dose
4th Event Dose
1
100%
100%
100%
100%
2
delay* then 100%
delay* then 75%
delay* then 50%
discontinue
3
delay* then 75%
delay* then 50%
discontinue
discontinue
4
discontinue or
delay* then 50%
discontinue
discontinue
discontinue
* delay until until resolved to grade 0-1 


Confidential
Page: 34
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
7.2.4
BBI608 
For any BBI608-related intolerable grade 3 or intolerable grade 2 adverse event, persisting despite
optimized medical management, a dose holiday of 1-3 days followed by dose modification is
recommended. Dose modification may include reduction of the total daily dose and/or in the number 
of doses taken per day. Investigators should discuss dose modifications with the medical monitor for 
the sponsor.  Patients may up-titrate dose to full dose as tolerated. 
If a toxicity is thought by the Investigator to be related to both BBI608 and the combination drug 
(Cetuximab, Panitumumab or Capecitabine), then the dose modification rules for both agents should
be followed.
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 actually ingested /number of capsules that should have been ingested per dose
level) x 100= % compliance 
Capecitabine compliance will be calculated using the following equation: 
(Number of capsules actually ingested /number of capsules that should have been ingested per dose
level) x 100= % compliance 
Cetuximab or Panitumumab compliance will be calculated using the following equation:
(Number of treatments performed /number of treatments that should have been performed per dose
level) 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.  Patients may receive palliative radiation therapy. 


Confidential
Page: 35
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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. 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
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 
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 
• 
Megestrol acetate (Megace®) 
• 
Dethamethasone
• 
Diphenhydramine 
• 
Cimetidine 
• 
Ranitidine 
7.6.2    Prohibited Treatment 
• 
Any  other concurrent  chemotherapy,  non-palliative radiotherapy,  hormonal  therapy,  or 
immunotherapy 
• 
Other investigational agents 
• 
Immunosuppressive therapies, including systemic corticosteroids (except when used 
intermittently in an antiemetic regimen or when prescribed at a non-immunosuppressive dose
for treatment of fatigue and low-appetite)


Confidential
Page: 36
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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, published 28 May 2009. 
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 
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.


Confidential
Page: 37
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 , except for events that are 
clearly disease related
• 
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 procedures 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 or facsimile. The reaction must be completely described on the CRF
and SAE report form. 
Primary Medical Monitor Contact information:
Matthew Hitron, MD 
Boston Biomedical, Inc 
640 Memorial Drive 
Cambridge, MA 02139  USA
Telephone:1- (617) 674-6800 ext. 8563 
Fax: (617) 674-8662
Emergency Number: 1-508-410-
5512
9   ASSESSMENT OF ANTI-TUMOR ACTIVITY IN SOLID TUMORS
The following definitions and criteria (from Response Evaluation Criteria in Solid Tumors [RECIST
1.1, Eisenhauer et al. 2009] 19 ) should be used for the baseline evaluations of existing disease, and for
the ongoing evaluation of tumor responses.
Measurable disease - the 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.
Matthew Hit
w
ron,
t
MD
,
Boston Biomedical, Inc 
,
640 Memorial Drive 
Cambridge, MA 02139  US
A
A
g ,
Telephone:1- (617) 674-6800 ext. 8563
-
Fax: (617) 674-8662
p
(
)
Emergency Number:
m
1-508-410-
5512


Confidential
Page: 38
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Non-measurable lesions - all other lesions, including small lesions (longest diameter <10 mm with
conventional techniques, <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 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
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. 
9.2
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. 


Confidential
Page: 39
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
9.3
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
9.4
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
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).


Confidential
Page: 40
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
10.2 Determination of Sample Size
The following number of colorectal cancer patients will be enrolled based on a two-stage Simon 
design with an alpha of 5% and a power of 80% to detect a disease control rate improvement for
Cetuximab and Panitumumab from about 30% (historical DCR for 3rd and 4th line colorectal cancer) 
to 60%, and a disease control rate improvement for Capecitabine from about 15% (historical DCR for
3rd line colorectal cancer) to 60%
Disease Control Rate – Third Line
Monotherapy 
(Historical)
Combination * 
(Historical)
Combination with BBI608 
(Expected)
Cetuximab
30-40% 4,5
~ 63% 10-15
60% or more
Panitumumab
30-40% 6-8
~ 68% 16
60% or more
Capecitabine
~ 15% 9
~ 45% 17,18
60% or more
* 
Cetuximab + Irinotecan
Panitumumab + Irinotecan
Capecitabine + Mitomycin C 
Simon two-stage design for Phase II
Patient number
Combo Therapy
Stage 1
Stage 2
Total*
Cetuximab
8
16
24
Panitumumab
8
16
24
Capecitabine
6
12
18
*If any of the three arms reach a DCR of 60% or more at the end of Simon Stage 2, a one-time option 
to expand accrual to a total sample size of up to 50 patients may be implemented for each arm. 
For the Cetuximab and Panitumumab combination cohorts, if the disease control rate in stage 1
reaches 3 of 8 or above, additional patients will be enrolled into the stage 2 cohort. For the 
Capecitabine combination cohort, if the disease control rate in stage 1 reaches 2 of 6 or above, 
additional patients will be enrolled into the stage 2 cohort. 
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. 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.


Confidential
Page: 41
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 disease control rate
and overall response. Progression-free survival and overall survival will be evaluated in the intent-to- 
treat population. Anti-tumor activity will be evaluated on an exploratory basis and will be
summarized using descriptive statistics or graphics.
10.4 Efficacy
The primary population for the efficacy evaluation will be the evaluable population, defined as
patients who have been treated with at least 80 % of 1 complete cycle of BBI608 and a combination 
drug. The primary efficacy outcome measure will be disease control rate, defined as the proportion of
patients with a documented complete response, partial response and stable disease (CR + PR + SD)
based on RECIST. In addition, progression-free survival (PFS) and overall survival (OS) will be 
obtained from intent-to-treat patients. PFS will be calculated from the date of patient enrolment into
the trial until documented disease progression based on RECIST. OS will be calculated from the date
of patient enrolment into the trial until death. 
10.5 Demographics and Baseline Characteristics
Patient characteristics will include a complete summary of the following and will be recorded in the 
CRFs:
• 
Patient demographics
• 
Baseline disease characteristics 
• 
Pre-existing conditions
• 
Prior therapies
• 
Concomitant medications and treatments 
Other patient characteristics will be summarized as appropriate 
10.6 Statistical Analysis of Pharmacokinetic Variables
Pharmacokinetics will only be performed on the first 6 patients enrolled in each combination arm of 
this study. 
Timed blood sample collection for BBI608 and Cetuximab pharmacokinetic analysis will be
performed on Days 5-11 and 26-32 after the first dose of Cycle 1 for the first 6 patients enrolled in the
Cetuximab arm. Timed blood sample collection for BBI608 and Panitumumab pharmacokinetic
analysis will be performed on Days 8-14 and 22-28 after the first dose of Cycle 1 for the first 6
patients enrolled in the Panitumumab arm. Timed blood sample collection for BBI608 and 
Capecitabine pharmacokinetic analysis will be performed on Days 8-9 and 21-22 after the first dose 
of Cycle 1 for the first 6 patients enrolled in the Capecitabine arm. 
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 noncompartmental and/or nonlinear least squares
regression using WinNonLin. Pharmacokinetic parameters, including Cmax, volume of distribution, 
distribution half-life, terminal half-life, and AUC will be evaluated.


Confidential
Page: 42
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
10.7 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 combination arm, 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.
10.8 Analysis and Sample size for sub-cohorts
Each sub-cohort will be analyzed for number of days of Grade II/III diarrhea and % treatment 
compliance achieved during the first two cycles. The % treatment compliance will be calculated as 
the number of capsules actually ingested over the number of capsules that should have been ingested 
per dose level multiplied by 100. The research questions addressed by sub-cohorts are hypothesis-
generating and exploratory in nature. Initially 6 subjects will be assigned to each sub-cohort to assess 
the effect of intervention. Selected sub-cohorts will be extended to enroll up additional 20 patients. 
The decision of extending the enrollment will be based on clinical assessment without formal 
statistical testing. However, 20 patients will give 80% power to detect 20% difference in % treatment 
compliance between two arms and 57% power to detect the difference of 25% in the number of days 
of having Grade II/III diarrhea using two-sided Z test with pooled variance at type I error rate of 0.15. 
The control rates assumed are 70% for treatment compliance and 30% for diarrhea. The patients will 
be sequentially allocated to different sub-cohorts by the Sponsor to avoid section bias.
11 QUALITY CONTROL AND ASSURANCE
The study will be initiated and conducted under the Sponsorship of BBI. The clinical supplies of 
BBI608 and CRFs will be supplied by BBI or its representative. Representatives of BBI 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. 
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 days prior to the 1st drug administration. At that time the combination arm 
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 but do not
qualify for the study or who do not receive study drug. The reason for disqualification should be 
noted in the log. 


Confidential
Page: 43
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
11.3 Removal, Replacement, or Early Withdrawals of Subjects
If a subject exits the study prior to receiving four weeks of BBI608 or does not receive four weeks of 
BBI608 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


Confidential
Page: 44
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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) (compliant  with
federal
regulations 21 CFR 56) 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, Health Canada 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 
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.


Confidential
Page: 45
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 the US federal regulations (21 CFR Part 50) and 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 per HIPAA from each subject, or if appropriate, the subject’s parent or 
legal guardian.
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 the FDA, and 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, 


Confidential
Page: 46
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 (listed 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 institutions(s) specified on form FDA 1572. 
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 drug is 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 drug, 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. 


Confidential
Page: 47
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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 Health Canada, or other regulatory bodies 
outside of Canada, such as the United States Food and Drug Administration 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.
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.


Confidential
Page: 48
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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
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


Confidential
Page: 49
October 9th, 2014
Amendment #2 
Boston Biomedical, Inc
Clinical Protocol BBI608-224
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.


Confidential
Page: 44
14 APPENDIX A: SCHEDULE OF ASSESSMENTS
BBI608 + Cetuximab
Tests & Procedures
Pre-Study
Evaluation
Study Evaluations1
End of Study Visit
Cycle 1
Cycle 2 & Beyond
Week
0
1
2
3
4
1
2
3
4
Day
0
1
5
8
12
19
26
5
12
19
26
 30 days from last 
BBI608 dose
Window
-7 ± 3 days
± 1 day
± 1 day
Medical history
X
Physical examination
X
X
X
Serum pregnancy test3
X
Karnofsky performance status
X
X
X
X
X
X
X
Vital signs, Weight
X
X
X
X
X
X
X
Hematology2
X
X
X
X
X
X
X
Blood chemistry2
X
X
X
X
X
X
X
Liver function tests2
X
X
X
X
X
X
X
Electrolytes2
X
X
X
X
X
X
X
Urinalysis2
X
X
X
X
X
X
12-Lead electrocardiogram
X
X
X
Tumor markers3
X
X
X
Tumor biopsy3
X
X
X
Pharmacokinetics (first 6 patients only)
X
X
Tumor measurement & staging4,5
X
6
X
7
Concomitant medications
X
X
X
X
X
X
X
Adverse events8
X
X
X
X
X
X
Dispense BBI608
X
X
X
X
X
X
Cetuximab infusion
X
X
X
X
X
X
X
X
1. Calculated from the date of first BBI608 dose. 
2. Refer to Section 6.3 for description of laboratory assessments. 
3. If applicable
4. Including tumor measurements, following RECIST 1.1.
5. Prior to cycle 3 and every other cycle thereafter, assessments must be made utilizing the same imaging method as baseline 
6. Unless CT/MRI has been performed within last three weeks 
7. Unless CT/MRI has been performed within last four 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.


Confidential
Page: 45
BBI608 + Panitumumab
Tests & Procedures
Pre-Study
Evaluation
Study Evaluations1
End of Study Visit
Cycle 1
Cycle 2 & Beyond
Week
0
1
2
3
4
1
2
3
4
Day
0
1
8
15
22
1
8
15
22
 30 days from last 
BBI608 dose
Window
-7 ± 3 days
± 1 day
± 1 day
Medical history
X
Physical examination
X
X
X
Serum pregnancy test3
X
Karnofsky performance status
X
X
X
X
X
Vital signs, Weight
X
X
X
X
X
Hematology2
X
X
X
X
X
Blood chemistry2
X
X
X
X
X
Liver function tests2
X
X
X
X
X
Electrolytes2
X
X
X
X
X
Urinalysis2
X
X
X
X
X
12-Lead electrocardiogram
X
X
X
Tumor markers3
X
X
X
Tumor biopsy3
X
X
X
Pharmacokinetics (first 6 patients only)
X
X
Tumor measurement & staging4,5
X
6
X
7
Concomitant medications
X
X
X
X
X
Adverse events8
X
X
X
X
Dispense BBI608
X
X
X
X
Panitumumab infusion
X
X
X
X
1.
Calculated from the date of first BBI608 dose. 
2.
Refer to Section 6.3 for description of laboratory assessments. 
3.
If applicable
4.
Including tumor measurements, following RECIST 1.1. 
5.
Prior to cycle 3 and every other cycle thereafter, assessments must be made utilizing the same imaging method as baseline 
6.
Unless CT/MRI has been performed within last three weeks. 
7.
Unless CT/MRI has been performed within last four 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.


Confidential
Page: 46
BBI608 + Capecitabine
Tests & Procedures
Pre-Study
Evaluation
Study Evaluations1
End of Study Visit
Cycle 1
Cycle 2 & Beyond
Week
0
1
2
3
4
1
2
3
4
Day
0
1
8
15
21
1
8
15
21
 30 days from last 
BBI608 dose
Window
-7 ± 3 days
± 1 day
± 1 day
Medical history
X
Physical examination
X
X
X
Serum pregnancy test3
X
Karnofsky performance status
X
X
X
X
X
X
Vital signs, Weight
X
X
X
X
X
X
Hematology2
X
X
X
X
X
X
Blood chemistry2
X
X
X
X
X
X
Liver function tests2
X
X
X
X
X
X
Electrolytes2
X
X
X
X
X
X
Urinalysis2
X
X
X
X
X
X
12-Lead electrocardiogram
X
X
X
Tumor markers3
X
X
X
Tumor biopsy3
X
X
X
Pharmacokinetics (first six patients only)
X
X
Tumor measurement & staging4,5
X6
X7
Concomitant medications
X
X
X
X
X
X
Adverse events8
X
X
X
X
X
Dispense BBI608
X
X
X
X
X
Dispense Capecitabine
X
X
1.
Calculated from the date of first BBI608 dose. 
2.
Refer to Section 6.3 for description of laboratory assessments. 
3.
If applicable
4.
Including tumor measurements, following RECIST 1.1. 
5.
Prior to cycle 3 and every other cycle thereafter, assessments must be made utilizing the same imaging method as baseline 
6.
Unless CT/MRI has been performed within last three weeks. 
7.
Unless CT/MRI has been performed within last four 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.


Confidential
Page: 47
15 APPENDIX C:  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.


Confidential
Page: 48
October 9th, 2014
Amendment #2
Boston Biomedical, Inc
Clinical Protocol BBI608-224
16 APPENDIX D:  PHARMACOKINETIC STUDIES
Instructions for Collecting and Processing Samples 
Sampling to define the plasma pharmacokinetics of BBI608 and Cetuximab, or Panitumumab
or Capecitabine will be performed in the first 6 patients enrolled in each combination arm of 
the study. For the Cetuximab arm, samples are taken on Day 5-12 and Day 26-33 of cycle 1. 
For the Panitumumab arm, samples are taken on Day 8-15 and Day 22-29 of cycle 1. For the 
Capecitabine arm, samples are taken on Day 8-9 and Day 21-22 of cycle 1. The sampling 
schedule 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 schedule has been devised to 
accommodate treatment on an outpatient basis. Dosing of the first dose of drug must be 
started before 10 a.m. on a Tuesday, Wednesday, or Thursday to facilitate the collection of
the pharmacokinetic samples at the scheduled times during the regular operating hours of the 
outpatient clinics.
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). Extraordinary caution should be taken to prevent hemolysis in the blood sample.
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 min 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.
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) 


Confidential
Page: 49
October 9th, 2014
Amendment #2
Boston Biomedical, Inc
Clinical Protocol BBI608-224
within 5-10 min after collection. Separate the plasma from the blood cells using a pipette 
and transfer approximately equal volumes into three 2 mL self-standing opaque 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, 100-120 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 placed in a subdirectory located on a secure network server. All members of
the clinical, laboratory, and administrative staff involved with phase II studies will be given 
read-only access to this subdirectory. The files are placed under the following subdirectories: 
PK_Time_Forms; PK_Tube_Labels. Files for the PK time forms are printed directly from 
the file stored on the network server for each subject study. Since changes may be
periodically made to these forms, they cannot be copied onto user personal computers and 
staff members are instructed not to make photocopies of blank forms. 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, then 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 are prelabeled. 
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 and Cetuximab, or Panitumumab or Capecitabine will be analyzed by
noncompartmental methods and/or nonlinear least squares regression using WinNonlin 
(Scientific Consulting, Inc.). Pharmacokinetic parameters and variables will be calculated 
according to standard equations. 


Confidential
Page: 50
October 9th, 2014
Amendment #2
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Cycle
No.
Sample
No.
Procedure
Desired Time
1
Draw blood sample
PK-01
-5 min
Start BBI608 administration
0 min
Draw blood sample
PK-02
30 min
Draw blood sample
PK-03
60 min
Draw blood sample
PK-04
120 min
Draw blood sample
PK-05
175 min
Start Cetuximab infusion
180 min
Draw blood sample
PK-06
240 min
Draw blood sample
PK-07
300 min
Draw blood sample
PK-08
360 min
Draw blood sample
PK-09
420 min
Draw blood sample
PK-10
480 min
Draw blood sample
PK-11
540 min
Draw blood sample
PK-12
24 hour
Draw blood sample
PK-13
27 hour
Draw blood sample
PK-14
99 hour
Draw blood sample
PK-15
171 hour
Pharmacokinetic Sample Collection (Cetuximab Arm)
Day 5-12 in CYCLE 1 ONLY
Day 26-33 in CYCLE 1 ONLY
Cycle
No.
Sample
No.
Procedure
Desired Time
1
Draw blood sample
PK-01
-5 min
Start BBI608 administration
0 min
Draw blood sample
PK-02
30 min
Draw blood sample
PK-03
60 min
Draw blood sample
PK-04
120 min
Draw blood sample
PK-05
175 min
Start Cetuximab infusion
180 min
Draw blood sample
PK-06
240 min
Draw blood sample
PK-07
300 min
Draw blood sample
PK-08
360 min
Draw blood sample
PK-09
420 min
Draw blood sample
PK-10
480 min
Draw blood sample
PK-11
540 min
Draw blood sample
PK-12
24 hour


Confidential
Page: 51
October 9th, 2014
Amendment #2
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Cycle
No.
Sample
No.
Procedure
Desired Time
1
Draw blood sample
PK-01
-5 min
Start BBI608 administration
0 min
Draw blood sample
PK-02
30 min
Draw blood sample
PK-03
60 min
Draw blood sample
PK-04
120 min
Draw blood sample
PK-05
175 min
Start Panitumumab infusion
180 min
Draw blood sample
PK-06
240 min
Draw blood sample
PK-07
300 min
Draw blood sample
PK-08
360 min
Draw blood sample
PK-09
420 min
Draw blood sample
PK-10
480 min
Draw blood sample
PK-11
540 min
Draw blood sample
PK-12
24 hour
Draw blood sample
PK-13
27 hour
Draw blood sample
PK-14
99 hour
Draw blood sample
PK-15
171 hour
Draw blood sample
PK-13
27 hour
Draw blood sample
PK-14
99 hour
Draw blood sample
PK-15
171 hour
Pharmacokinetic Sample Collection (Panitumumab Arm)
Day 8-15 in CYCLE 1 ONLY
Day 22-29 in CYCLE 1 ONLY
Cycle
No.
Sample
No.
Procedure
Desired Time
1
Draw blood sample
PK-01
-5 min
Start BBI608 administration
0 min
Draw blood sample
PK-02
30 min
Draw blood sample
PK-03
60 min
Draw blood sample
PK-04
120 min
Draw blood sample
PK-05
175 min
Start Panitumumab infusion
180 min
Draw blood sample
PK-06
240 min


Confidential
Page: 52
October 9th, 2014
Amendment #2
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Draw blood sample
PK-07
300 min
Draw blood sample
PK-08
360 min
Draw blood sample
PK-09
420 min
Draw blood sample
PK-10
480 min
Draw blood sample
PK-11
540 min
Draw blood sample
PK-12
24 hour
Draw blood sample
PK-13
27 hour
Draw blood sample
PK-14
99 hour
Draw blood sample
PK-15
171 hour
Pharmacokinetic Sample Collection (Capecitabine Arm)
Day 8-9 in CYCLE 1 ONLY
Cycle
No.
Procedure
Sample
No.
Desired Time
1
Draw blood sample
PK-01
-5 min
Start BBI608 administration
0 min
Draw blood sample
PK-02
30 min
Draw blood sample
PK-03
60 min
Draw blood sample
PK-04
120 min
Start Capecitabine
administration
175 min
Draw blood sample
PK-05
180 min
Draw blood sample
PK-06
240 min
Draw blood sample
PK-07
300 min
Draw blood sample
PK-08
360 min
Draw blood sample
PK-09
420 min
Draw blood sample
PK-10
480 min
Draw blood sample
PK-11
540 min
Draw blood sample
PK-12
600 min
Draw blood sample
PK-13
660 min
Draw blood sample
PK-14
24 hour
Pharmacokinetic Sample Collection (Capecitabine) 
Day 21-22 in CYCLE 1 ONLY
Cycle
No.
Procedure
Sample
No.
Desired Time
1
Draw blood sample
PK-01
-5 min


Confidential
Page: 53
October 9th, 2014
Amendment #2
Boston Biomedical, Inc
Clinical Protocol BBI608-224
Start BBI608 administration
0 min
Draw blood sample
PK-02
30 min
Draw blood sample
PK-03
60 min
Draw blood sample
PK-04
120 min
Start Capecitabine
administration
175 min
Draw blood sample
PK-05
180 min
Draw blood sample
PK-06
240 min
Draw blood sample
PK-07
300 min
Draw blood sample
PK-08
360 min
Draw blood sample
PK-09
420 min
Draw blood sample
PK-10
480 min
Draw blood sample
PK-11
540 min
Draw blood sample
PK-12
600 min
Draw blood sample
PK-13
660 min
Draw blood sample
PK-14
24 hour


Confidential
Page: 54
17 APPENDIX E: 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. Submission of paraffin embedded tissue blocks to Boston Biomedical is 
preferred. However, if tumor blocks are not available, 20 positively charged, unstained tissue 
slides at 5 micron thickness should be sent to Boston Biomedical. 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. 
Fresh Tumor Biopsies:
Patients who are identified by the principal investigator as having a lesion, which could be 
biopsied with a minimally invasive technique, will be asked to sign an additional consent. 
Tumor biopsy samples should be collected at baseline and 4 hours after administration of 
BBI608 on Day 8 of cycle 1. Tumor biopsies will be collected for immunohistochemitry- 
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 by the hospital pathology 
department using their 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 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 and sterilely placed 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 


Confidential
Page: 55
Boston Biomedical, Inc 
October 9th, 2014
Clinical Protocol BBI608-224 
Amendment #2 
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. 
Shipping information:
Please ship all tumor samples to the following address: 
Youzhi Li, MD. 
Boston Biomedical, Inc. 
640 Memorial Drive 
Cambridge, MA 02139 USA 
Phone: 617-674-6800 x8574 
Fax: 
(617) 674-8662 
Email: yli@bostonbiomedical.com
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.
Youzhi Li, MD.
Boston Biomedical, Inc. 
,
640 Memorial Drive 
Cambridge, MA 02139 USA 
g ,
Phone: 617-674-6800 x8574 
Fax: 
(617) 674-8662
(
)
Email: yli@bostonbiomedical.com


Confidential
Page: 56
18 APPENDIX F: CETUXIMAB, PANITUMUMAB AND CAPECITABINE 
PRODUCT LABELS




Confidential
Page: 58
October 9th, 2014
Amendment #2
Boston Biomedical, Inc
Clinical Protocol BBI608-224
21 REFERENCES
1.
Lobo et al, (2007) Annu Rev Cell Dev Biol 23:675-699. 
2.
Boman and Wicha, (2008) J Clin Oncol. 26:2795-2799.
3.
Please find a list of updated reviews on cancer stem cells in all major cancer types in the June 10
special issue of Journal of Clinical Oncology on cancer stem cells (J Clin Oncol. 2008 Jun 
10;26(17)).
4.
Jonker et al, New Engl J Med. (2007) 357:2040-2048 
5.   Lenz et al, J Clin Oncol. (2006) 24:4914-21.
6.
Van Cutsem et al, J Clin Oncol. (2007) 25:1658-1664. 
7.
Van Cutsem et al, Annal Oncol. (2008) 19:92-98.
8.   Hecht et al, Cancer  (2007) 110:980-988.
9.
Gubanski et al, Acta Oncol. (2005) 44:236-239.
10. Spindler et al, BMC Cancer (2011) 11:107.
11. Gebbia et al, Clin Colorectal Cancer (2006) 5:422-428. 
12. Vincenzi et al, Br J Cancer (2006) 94:792-797. 
13. Pfeiffer et al, Acta Oncol (2007) 46:697-701. 
14. Sobero et al, J Clin Oncol. (2008) 26:2311-2319. 
15. Garm Spindler et al, Ann Oncol. (2009) 20 :879-884.
16. Chibaudel et al, J Clin Oncol. (2011) 29:suppl; abstr 3573. 
17. Chong et al, Br J Cancer (2005) 93:510-514. 
18. Lim et al, Cancer Chemother Pharmacol. (2005) 56:10-14.
19. Eisenhauer et al. Eur J Cancer (2009) 45:228-47.

SAP_001.pdf: 
 
 
Protocol BBI608-224 
A Phase II Clinical Study of BBI608 in Adult Patients
with Advanced Colorectal Cancer  
Statistical Analysis Plan
(SAP)
Version: Amendment 3 
  
Author: Yanqiu Weng, Jay Hu  
Date: 9 September 2020 
 
 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 2 
 
 
 
 
Protocol BBI608-224 
STATISTICAL ANALYSIS PLAN APPROVAL 
Approved by:
_________________________________________ Date: _____/_____/_________ 
Suha Sari, PhD 
Director of Biostatistics
_________________________________________ Date: _____/_____/_________ 
Lucia Archiable
Medical Director of Drug Safety and Pharmacovigilance  
 
_________________________________________ Date: _____/_____/_________ 
Matthew Hitron, MD 
Executive Medical Director of Clinical Development
 
 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 3 
 
 
 
Contents 
1. Amendments from Previous Version(s) .................................................................................................... 5 
2. Introduction .............................................................................................................................................. 5 
2.1. Study Design....................................................................................................................................... 5 
2.2 Study Objectives ................................................................................................................................. 6 
2.1.1. Primary Objectives ...................................................................................................................... 6 
2.1.2. Secondary Objectives .................................................................................................................. 7 
3. Endpoints and covariates: Definitions and Conventions .......................................................................... 7 
3.1. Primary Endpoint(s) ........................................................................................................................... 7 
3.2. Secondary Endpoints ......................................................................................................................... 7 
3.3. Other Endpoints ................................................................................................................................. 8 
3.4. Covariates .......................................................................................................................................... 8 
4. Hypotheses and decision rules ................................................................................................................. 8 
4.1. Statistical Hypotheses ........................................................................................................................ 8 
4.2. Statistical Decision Rules .................................................................................................................... 8 
4.2.1. DLT Decision Rule ........................................................................................................................ 8 
4.2.2. Simon’s Design Decision Rule ..................................................................................................... 9 
4.3. Sample Size Justification .................................................................................................................... 9 
5. Interim Analyses ........................................................................................................................................ 9 
6. Analysis Sets .............................................................................................................................................. 9 
6.1. Full Analysis Set .................................................................................................................................. 9 
6.2. Safety Analysis Set ............................................................................................................................. 9 
6.3. Response Evaluable Set ..................................................................................................................... 9 
6.4. PK Analysis Set ................................................................................................................................... 9 
7. DATA Handling ........................................................................................................................................ 10 
7.1. Methods for Handling Missing Dates ............................................................................................... 10 
7.2. Definition of Baseline Values .......................................................................................................... 11 
7.3. Windowing of Visits ......................................................................................................................... 11 
7.4. Withdrawals, Dropouts, Loss to Follow-up ...................................................................................... 11 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 4 
 
 
7.5. Pharmacokinetics ............................................................................................................................. 11 
7.6. Pharmacodynamic parameters ........................................................................................................ 12 
8. Statistical Methodology and StatistIcal Analyses ................................................................................... 12 
8.1. Statistical Methods .......................................................................................................................... 12 
8.1.1. Analysis for Time-to-Event Data ............................................................................................... 12 
8.1.2. Analysis for Binary Data ............................................................................................................ 12 
8.1.3. Analysis for Continuous Data .................................................................................................... 12 
8.2. Statistical Analyses ........................................................................................................................... 12 
8.2.1. Standard Analysis ..................................................................................................................... 13 
8.2.2. Analysis for Primary Endpoint ................................................................................................... 16 
8.2.3. Analysis for Secondary Endpoints ............................................................................................. 16 
8.2.4. Safety Analyses ......................................................................................................................... 18 
9. References .............................................................................................................................................. 22 
10. APPENDICES .......................................................................................................................................... 23 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 5 
 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
This is the amendment 1 of the statistical analysis plan (SAP).
Version
Date
Author(s)
Summary of Changes/Comments
Version 1.0
17SEP2018
Yue Chang
Statistical Analysis Plan 
Amendment 1
15Nov2019
Yanqiu Weng
Clarification of statistical methods
Amendment 2
02Mar2020
FMD
Address biostat comments
Amendment 3
09Sep2020
Jay Hu
Address some internal comments 
2. INTRODUCTION
This statistical analysis plan (SAP) describes the statistical methods that will be used for the
analyses of the clinical study report (CSR) for Boston Biomedical Protocol BBI608-224.This SAP 
should be read in conjunction with the study protocol and electronic case report forms (eCRFs). 
This version of the SAP has been developed using up to Protocol amendment 2 dated 09Oct2014. 
2.1. Study Design
This is an open label, multi-center, Phase II study of napabucasin (BBI608) administered in
combination with either cetuximab, or panitumumab, or capecitabine to patients with advanced
colorectal cancer. The study is designed to explore the safety, tolerability, preliminary anti-tumor 
activity and pharmacokinetics of napabucasin when administered in combination with each one of 
the above regimens. 
Six patients would be initially enrolled in each combination arm at a napabucasin dose level of 
500 mg BID (1000 mg total daily using 50 mg capsules) before protocol amendment 2 or 480 mg 
twice daily (960 mg total daily dose) using 80 mg capsules after protocol amendment 2. If  1 out 
of 6 patients had an observable dose limiting toxicity (DLT) in the combination regimen, then that 
arm of the study would continue to enroll patients at 500 mg BID (1000 mg total daily) using 50 
mg capsules or 480 mg BID (960 mg total daily) using 80 mg capsules following a Simon 2-stage 
design.  If a DLT occurred in  2 of the 6 patients in a combination arm, then that arm of the study 
would be closed and no further patients would be enrolled. A given arm of napabucasin in 
combination with cetuximab, or panitumumab, or capecitabine would continue to enroll patients 
if no more than 1 out of 6 patients in the combination arm had an observable DLT.    
The number of colorectal cancer patients enrolled would be based on a two-stage Simon design 
and is presented in Section 4.1 of the protocol amendment 2 [5]. If any of the three arms reach a 
disease control rate (DCR) of 60% or higher at the end of the Simon Stage 2 portion of the study,
a one-time option to expand accrual to a total sample size of up to 50 patients may be implemented 
for each arm.
To evaluate the tolerability of napabucasin, patients from each arm would be assigned to one of 4 
sub-cohorts (with 6 patients in each sub-cohort: IA, IB, IIA, IIB) from protocol amendment 2. The 
evaluation of tolerability would be done at selected centers for the study arm that was continuing 
patient accrual and in which a total of 50 evaluable patients had not been reached. For each 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 6 
 
 
combination arm, patients assigned to sub-cohorts IA and IB would receive napabucasin at 240 
mg twice daily (480 mg total daily dose) starting on Day 1 of Cycle 1. Intra-patient dose escalation 
of napabucasin to 480 mg twice daily (960 mg total daily dose) was allowed for patients in these 
cohorts as tolerated. Patients assigned to sub-cohorts IIA and IIB would receive napabucasin at 
480 mg twice daily (960 mg total daily dose) starting on Day 1 of Cycle 1. In the event of toxicity, 
dose adjustment of napabucasin was permitted, as recommended in dose modification guidelines. 
Additionally, patients assigned to sub-cohorts IA and IIA would receive prophylactic anti-
diarrheal treatment starting the day prior to Day 1 of Cycle 1. Patients assigned to sub-cohorts IB 
and IIB would receive anti-diarrheal treatment on an as-needed basis starting with development of 
diarrhea (ie, any occurrence greater than the patient’s baseline). For each combination regimen, 
patients would be sequentially assigned to each of the 4 sub-cohorts in the following order until 6 
patients were accrued in each of the sub-cohorts: IA, IB, IIA, and IIB. If required, up to an
additional 20 patients might be assigned to selected sub-cohorts to validate the observations in the 
initial 6 patients.  
Table 1 Tolerability Analysis of Napabucasin 
Sub-cohort
Napabucasin Starting Dose Level 
Anti-diarrheal Administration* 
IA
240 mg bid (480 total daily dose)1
Prophylactic 
IB
240 mg bid (480 total daily dose)1
As needed
IIA
480 mg bid (960 total daily dose)2
Prophylactic 
IIB
480 mg bid (960 total daily dose)2
As needed
1Intra-patient dose escalation of napabucasin to 480 mg po twice daily (960 mg total daily dose) is allowed as tolerated.
2In case of toxicity, dose adjustment of napabucasin is permitted.
*See protocol amendment 2 [5] section 7.1.4 for details
A study cycle would consist of 28 days of daily administration of napabucasin in combination 
with cetuximab or panitumumab, or capecitabine. Cycles would continue until unacceptable 
toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.
Pharmacokinetic (PK) assessments would be performed on the first 6 patients enrolled in each 
combination arm. Pharmacodynamic assessments would be performed in patients with readily 
accessible tumor tissue through an optional tumor biopsy. Evaluation of anti-tumor activity 
would be performed at 8-week intervals per RECIST 1.1 while patients remain on study. 
2.2 Study Objectives
2.1.1. Primary Objectives
To determine the safety and preliminary anti-tumor activity of napabucasin when administered
in combination with cetuximab, or panitumumab, or capecitabine in adult patients with advanced
colorectal cancer who have failed first- and second-line treatment.  
The primary endpoint is disease control rate, defined as the proportion of patients with a 
documented complete response, partial response and stable disease (CR + PR + SD) based on 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 7 
 
 
RECIST 1.1. The secondary endpoints include progression-free survival (PFS) and overall survival 
(OS).
2.1.2. Secondary Objectives
The secondary objectives of this study are as follows: 
x
To determine the pharmacokinetic profile of napabucasin and cetuximab, or 
panitumumab, or capecitabine when administered in combination. 
x
To determine the pharmacodynamics (biomarkers) of napabucasin. 
x
To evaluate tolerability of two dosing regimens of napabucasin by comparing 
administration of napabucasin at a 240 mg twice daily starting dose and escalating to 480 
mg twice daily after Cycle 1 versus administration of napabucasin at a 480 mg twice daily 
starting dose with dose adjustment permitted.
x
To evaluate tolerability of napabucasin by comparing prophylactic administration of 
anti-diarrheal medication versus as-needed administration of anti-diarrheal medication. 
The tolerability will be assessed using the adverse event profile and achieved dose intensity.
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS
3.1. Primary Endpoint(s)
x
Disease Control Rate (DCR), defined in section 2.1.1 
3.2. Secondary Endpoints
x
PK parameters of napabucasin administered in combination with cetuximab, or
panitumumab, or capecitabine. 
x
PK parameters of capecitabine and metabolite (5-FU). 
x
Pharmacodynamics parameters (or biomarkers) of napabucasin
administered in 
combination with cetuximab, or panitumumab, or capecitabine. Response (increase or 
decrease) of several biomarkers of napabucasin from biopsied tumors following 
napabucasin administration will be examined in patients with accessible tumors who 
consent to an optional biopsy. 
x
Objective Response Rate (ORR)
ORR is defined as the percentage of patients with a best overall response (BOR) of 
complete response (CR) or partial response (PR). The categorizations of response (CR, PR, 
SD, PD, and NE) and the derivations of BOR is provided in Appendix 1.1 and 1.2. 
x
Progression Free Survival (PFS) and Overall Survival (OS) 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 8 
 
 
PFS is defined as the time from the date of first treatment (or date of enrollment in 
sensitivity analysis) to the date of first documentation of progressive disease (PD) or death 
due to any cause, whichever occurs first.
OS is defined as the time from the date of treatment (or date of enrollment in sensitivity 
analysis) to the date of death. Patients without documentation of death at the time of 
analysis will be censored at the date last known to be alive. 
x
Dose Limiting Toxicities (DLTs): For definition of DLT, see Section 4.5 of the protocol 
amendment 2 [5].
3.3. Other Endpoints 
x
Adverse Events (AEs) characterized by type, frequency, severity (graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 
4.0], timing, seriousness, and relationship to study therapy
x
Laboratory abnormalities characterized by type, frequency, severity (graded by NCI
CTCAE version 4.0), and timing. 
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. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There is no hypothesis testing in this study. 
4.2. Statistical Decision Rules
4.2.1. DLT Decision Rule
DLT decisions are based on the observed number of patients with DLT at 480 mg BID 
napabucasin. 
Number of Patients with 
DLT at 480 mg bid
DLT Decision Rule
 1 out of 6
Continue patient enrollment in combination arm
> 2 out of 6
Close combination arm of the study


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 9 
 
 
4.2.2. Simon’s Design Decision Rule
The Simon’s design decision rule is described in Section 4.1 of protocol amendment 2 [5], but the 
study was not conducted following the Simon two-stage design and no Simon’s design decision 
rule was applied.  
4.3. Sample Size Justification
The sample size for this study was determined by clinical rather than statistical considerations.  
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 up to a total of approximately 
50 response evaluable patients will be enrolled in each combination arm during the study. Patients 
who have received at least one cycle of study treatment unless discontinued due to death or PD
and have had at least one disease assessment following the initiation of therapy will be considered 
evaluable for response.
5. INTERIM ANALYSES
No formal interim analyses are planned for this study. 
6. ANALYSIS SETS
6.1. Full Analysis Set
The full analysis set (FAS) includes all enrolled patients.  
6.2. Safety Analysis Set 
The safety population is defined as all patients who receive at least 1 dose of any study drug. The 
safety population will be used for all safety-related analyses such as AEs, concomitant medications, 
laboratory tests, and vital signs. 
6.3. Response Evaluable Set
The response evaluable set is defined as patients who have received at least one cycle of study 
treatment unless discontinued early due to death or PD and have had at least one disease assessment 
following the initiation of therapy. At least one cycle of study treatment is defined as at least 80% 
daily treatment compliance at targeted dose level during one cycle (cycle 1 or cycle 2) period prior 
to the first post-dosing imaging assessment. The response evaluable set will be used for analyses 
of disease control rate and overall response. 
6.4. PK Analysis Set
The napabucasin PK analysis dataset will include all patients who received at least one dose of 
napabucasin and have at least one quantifiable concentration.


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 10
 
 
The capecitabine and 5-fluorouracil PK analysis datasets will include all patients who received at 
least one dose of capecitabine and have at least one quantifiable concentration.
7. DATA HANDLING
7.1. Methods for Handling Missing Dates
For patient data listings, no imputation of incomplete dates will be applied. The listings will present 
incomplete dates without any change. 
Missing or Partial Death Dates 
Completely missing death dates will be imputed as the day after the date of last contact. 
A death date missing month and day will be imputed as Jan 1st of the year or the date after the date 
of last contact, whichever comes last. 
A death date missing day will be imputed as the 1st of the month or the day after the date of last 
contact, whichever comes last. 
Date of Last Dose of Study Drug 
No imputation will be done for first dose date. No imputation will be done for the date of last dose 
for patients off study. Date of last dose will be imputed by the analysis cutoff date for ongoing 
patients.
Date of Start of New Anti-Cancer Therapy
Incomplete dates for start date of new anti-cancer therapy will be imputed as follows and will be 
used for determining censoring dates for efficacy analyses: 
x
Completely missing start date will be imputed as the day after study treatment 
failure/relapse/PD, or the end date of new anti-cancer therapy if available, whichever
comes first
x
Start date missing both month and day will be imputed as Dec 31st of the year , or the end 
date of new anti-cancer therapy if available, whichever comes first
x
Start date missing day will be imputed as the last date of the month, or the end date of new 
anti-cancer therapy if available, whichever comes first
Missing Dates in Adverse Events/Concomitant Therapies
Every effort will be made to avoid missing/partial dates in on-study data. Start dates of adverse 
events/concomitant therapies will be imputed as follows:
x
Completely missing start date will not be imputed . 
x
Start date missing both month and day will be imputed as: 
o
the date of first dose if the year of the start date is the same as the date of first dose; 
o
otherwise, Jan 1st of the year of the start date will be used. 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 11
 
 
x
Start date missing day will be imputed as: 
o
the date of first dose if the year and month of the start date are the same as the date of 
first dose; 
o
otherwise, the 1st of the month of the start date will be used.
Stop dates of adverse events/concomitant therapies will be imputed as follows:
x
Completely missing stop date will not be imputed. 
x
Stop date missing both month and day will be imputed as Dec 31st of the year of stop date. 
x
Stop date missing day will be imputed as the last date of the month of the stop date. 
After imputation, the imputed date will be compared against the date of death, if available. If the 
planned imputed date is later than the date of death, the date of death will be used as the imputed 
date instead. In any cases above, if the imputed start date is after the end date, then set the start 
date the same as the end date.
7.2. Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but on or prior to, the start of study drug administration. CT and MRI scans may be considered 
for baseline assessment only if they were performed within 30 days of the first dose of napabucasin.
7.3. Windowing of Visits 
All data will be categorized based on the scheduled visit at which it was collected.  These visit 
designators are predefined values as used in the eCRF.   
7.4. Withdrawals, Dropouts, Loss to Follow-up
Time to event parameters will be censored if patients withdraw, drop out, or are lost to follow-up 
before documentation of the events (progressive disease / death).  Rules for censoring for PFS 
are detailed in Appendix 1.3. 
7.5. Pharmacokinetics
For individual concentration-time plots and the calculation of PK parameters using 
noncompartmental analysis, individual below the limit of quantification (BLQ) values will be 
converted using the following rules: 
x
If a BLQ value occurs in a profile before the first quantifiable concentration, it will be 
assigned a value of zero.
x
If a BLQ value occurs after a quantifiable concentration in a profile and is immediately 
followed by a value above the lower limit of quantification (LLQ), then the BLQ value 
should be treated as missing. 
x
If a BLQ value occurs at the end of the collection interval (after the last quantifiable 
concentration) it will be treated as missing.


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 12
 
 
x
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.
7.6. Pharmacodynamic parameters
Missing data for the pharmacodynamic parameters will be treated as such and no imputed values 
will be derived. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
Whilst every effort has been made to pre-specify all analyses in this statistical analysis plan, if 
additional exploratory analyses are found to be necessary, the analyses and the reasons for them 
will be detailed in the clinical study report (CSR).
8.1.1. Analysis for Time-to-Event Data
Time-to-event endpoints will be summarized using the Kaplan-Meier (KM) method [3] and 
displayed graphically when appropriate. Median event times and 2-sided 95% confidence intervals 
for each time-to-event endpoint [2] will be provided. KM analysis will only be performed if the 
number of events is no less than 5. 
8.1.2. Analysis for Binary Data 
Point estimates of binary endpoints will be provided for each treatment arm along with the 
corresponding 2-sided 95% confidence intervals using an exact method [1].  
8.1.3. Analysis for Continuous Data 
Descriptive statistics, such as the mean, standard deviation, coefficient of variation, median, 
minimum, and maximum values will be provided for continuous endpoints. Linear or non-linear 
models may be employed to analyze the continuous data.  
8.2. Statistical Analyses  
In general, all data will be summarized by arm and sub-cohort, unless otherwise specified. 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 13
 
 
8.2.1. 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 study, and primary 
reason to discontinue from the study. The summary will be based on the FAS.
Demographic and Baseline Characteristics
Baseline characteristics such as demographics, prior medication, medical history, Eastern 
Cooperative Oncology Group (ECOG) performance status, and primary diagnosis will be tabulated
for the safety set and listed for the FAS.  
x
Demographics: Demographics will be summarized in a descriptive fashion.  Baseline 
demographic data to be evaluated will include age, sex, race, height, weight, and other 
parameters as appropriate. Patient enrollment by region and country may be summarized.
x
Baseline disease characteristics: ECOG performance status, stage at study entry, and 
K-RAS mutation status. 
Prior and Concomitant Medications
Prior and concomitant medications will be coded to ATC (Anatomical Therapeutic Chemical) 
classification and Drug Name using WHO Drug Dictionary (WHO-DD) (March 2015). 
Medications that start and stop prior to the date of first treatment administration (either 
napabucasin or backbone chemotherapy, whichever is administered first) will be classified as 
‘prior’ medications. If a medication starts on or after the date of first treatment administration, 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 term using frequencies and percentages for the safety analysis set. Additional 
summary of concomitant medication will be provided by preferred name base and drug class. 
Prior Cancer Treatment
Prior cancer treatment included surgery plus radiotherapy and hormone /biologic/ chemotherapy
/other treatments, where the former will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®) version 18.0 and the latter will be coded using WHO Drug.  
Prior cancer treatment may be summarized by System Organ Class (SOC) and Preferred Term (PT)
as appropriate for each patient in the safety analysis set.
Medical History
Medical history will be coded by SOC and PT using the MedDRAversion 18.0 prior to the analysis.
Medical history will be summarized by SOC and PT using the number and percentage of patients 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 14
 
 
for the safety analysis set. 
Duration of Overall Survival Follow-up
The duration of overall survival (OS) follow-up is defined as time from the date of first treatment
to death or the last known alive visit. The median follow-up time for OS and the corresponding 
95% confidence interval (using the method of Brookmeyer and Crowley, 1982 with the log-log 
transformation) will be summarized using the reverse Kaplan-Meier (KM) method for the safety 
set. The analysis involves the event and censoring rules to be switched (ie, the patients who die
become ‘censored’, and the censored patients are treated as the ‘event’).  
Summaries of the number and percentage of patients who have died, those still in survival follow-
up, those lost to follow-up, and those who have withdrawn consent will be also provided. 
Extent of Exposure 
Exposure may be summarized as dose received (cumulative dose or actual dose intensity) or as 
dose received relative to the intended dose (relative dose [RD], or relative dose intensity [RDI]), 
or both.   
The information that will be summarized depends on how the study drug is dosed (eg, infusion 
cyclical, oral daily, oral cyclical).  
In what follows, “time unit” can be weeks or days.
Actual treatment duration = actual end of treatment date – date of first dose of study drug + 1, 
where
x
For napabucasin and Capecitabine, the actual end of treatment date is the last dosing date
x
For cyclic combination drugs in Arms A and B, actual end of treatment date = last dose of 
cyclic dosing + interval - 1, where interval = 7 for Arm A and interval =14 for Arm B. 
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
By cycle actual DI (dose unit/week) = [cumulative dose in the cycle]/ [actual cycle
duration in weeks] 
x
Overall actual DI (dose unit/week) = [overall cumulative dose] / [actual treatment 
duration in weeks] 
x
Note that actual DI for cyclical dosing is calculated based on actual cycle duration in all but the 
last cycle where it is fixed at the intended duration. 
Relative Dose Intensity (RDI): The basic intent is to evaluate dose per time unit factoring in 
dose reductions, interruptions, or delays.   


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 15
 
 
Relative dose intensity (RDI) by cycle and overall 
o
Intended DI (dose unit/time unit) = [intended cumulative dose per cycle] / [intended 
number of time units in a cycle]  
o
By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]  
o
Overall RDI (%) = 100 × [overall actual DI] / [intended DI]  
Note the intended dose level is fixed at the start of treatment rather than the start of a cycle
x
One exception is for Cetuximab. For Cetuximab, dose level is permitted to change from 
400 mg/m2 on day 5 in cycle 1 to 250 mg/m2 for each subsequent infusion. If dose level 
decreases for Cetuximab 4-7 days after first dose date, then updated dose level is the new 
intended dose level for Cetuximab.  
x
Second exception is for all backbone therapies. All backbone therapies incorporate BSA 
or weight to calculate each dose. Panitumumab incorporates weight to calculate each 
dose—all other therapies incorporate 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 Panitumumab, 
the last available weight prior to each infusion will be used for calculating each dose. 
x
BSA [m2] = ((Height [cm] × Weight [kg])/3600) × 0.5
x
Calculated doses will be rounded to the nearest integer 
x
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.
The intended cumulative dose of napabucasin per cycle is calculated by (intended dose level per 
day) × (intended cycle duration in days) 
x
Intended dose level per day for napabucasin is 500mg po BID 
Dose unit of napabucasin is mg, dose unit of other combination drugs (except Panitumumab) is 
mg/m2, dose unit of Panitumumab is mg/kg.
Treatment compliance
Treatment compliance for napabucasin is defined as follows:
(Cumulative actual total dose / total planned or intended dose) × 100 = % compliance 
For any IV combination drug (Cetuximab and Panitumumab), compliance will be calculated using 
the following equation: 
(Number of treatments administered / number of treatments that should have been 
administered) × 100 = % compliance
For oral combination drug (Capecitabine), compliance will be calculated using the following 
equation: 
(Cumulative actual total dose / total planned or intended dose) × 100 = % compliance 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 16
 
 
Daily treatment compliance will be reported for each patient by dose level cohort.
x
The % of days the patient received full daily dose of napabucasin or higher 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. 
x
The % of days the patient received full daily dose of napabucasin or higher out of the first 
56 days from treatment start.
x
The % of days the patient received a non-zero dose of napabucasin out of the first 56 days 
from treatment start.
Daily treatment compliance will be grouped according to the following categories: < 60%, 
t 60% - < 80%, t 80% - < 90%, t 90%, and will be summarized for all arms.   
8.2.2. Analysis for Primary Endpoint 
The primary endpoint is DCR, which is defined as the proportion of patients with a documented 
complete response (CR), partial response (PR), and stable disease (SD). The categorization of 
response (CR, PR, SD, PD, and NE) and the derivations of BOR are provided in Appendix 1.1. 
DCR will be summarized by arm and sub-cohort for the response evaluable set. DCR point 
estimates will be provided along with the corresponding 2-sided 95% confidence intervals using 
an exact method [1]. Sensitivity analysis of DCR will be performed for all patients in the safety 
set.
8.2.3. Analysis for Secondary Endpoints
8.2.3.1. PK Analysis 
Nuventra Pharma Sciences will compute PK parameters by noncompartmental analysis using 
Phoenix WinNonlin version 8.1 (Certara, Princeton, NJ), and generate TLFs 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 arm and cohort.
8.2.3.1.1. 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. 
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
therapy, as appropriate.  


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 17
 
 
8.2.3.1.2. Pharmacokinetic parameters 
PK parameters for napabucasin, including maximum concentration at steady state (Cmax,ss), the 
timepoint when Cmax was observed (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 terminal elimination half-life (t1/2) will be listed and summarized 
using descriptive statistics, including N, mean, standard deviation, CV, geometric mean, geometric 
CV, minimum, maximum, and median. For Tmax, N, minimum, maximum, and median will be 
reported. Parameters will be summarized by day, napabucasin dose, concomitant therapy and 
cohort. 
PK parameters for capecitabine and metabolite 5-FU, including maximum concentration after a 
single dose (Cmax), the timepoint when Cmax was observed (Tmax), area under the plasma 
concentration time curve from zero to the last quantifiable concentration (AUClast), area under 
the plasma concentration time curve from zero extrapolated to infinity (AUCinf), total body 
clearance (CL/F) volume of distribution during the terminal elimination phase (Vz/F), and t½, will 
be listed and summarized using descriptive statistics, including N, mean, standard deviation, CV, 
geometric mean, geometric CV, minimum, maximum, and median. For Tmax, N, minimum, 
maximum, and median will be reported. Parameters will be summarized by day and napabucasin 
dose. 
Napabucasin PK parameters will be estimated using actual elapsed time from napabucasin dosing. 
PK parameters of capecitabine and metabolite 5-FU will be estimated using actual elapsed time 
from capecitabine dosing.  Imputation of concentration data for BLQ is described in Section 7.5. 
8.2.3.2. PD/Biomarker Analysis 
Tumor archival tissues and biopsies will be collected as described in the protocol amendment 2 [5] 
Section 6.5.  A listing of tumor biomarkers may be provided if data are available.
Additional analyses of safety and/or efficacy may be performed in subsets defined by biomarker 
status as determined by evaluation of archival tissue.   
8.2.3.3. Other Efficacy Endpoints Analysis
Summary tables of Objective Response Rate (ORR), Progression Free Survival (PFS), and Overall 
Survival (OS) will be provided by arm and sub-cohort. The ORR will be summarized for the 
response evaluable set and safety set. The PFS and OS will be summarized with KM method for 
all patients in the safety set with start day calculated from the date of first treatment. Sensitivity 
analysis may be considered for PFS and OS based on the FAS with start day calculated from the 
date of patient enrollment if data are available. KM analysis will not be conducted if the number 
of events is less than 5. 
Efficacy listings to be provided include best response, first CR/PR date, last date with CR or PR, 
most recent date without progression, progression date, death date, date of first response and last
tumor assessment date, etc.
Swimmer plots for individual response and time on treatment,
waterfall plots for individual tumor size percent change from baseline, and spider plots for 
individual tumor size percent change from baseline over time may also be presented.


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 18
 
 
The following table provides an overview of the efficacy analysis.
Endpoint
Analysis Set
Statistical Method
Missing Data
Response (DCR, 
ORR, CR, PR)
Efficacy
Exact CI
Observed case
Overall Survival (OS)
Efficacy
Kaplan-Meier
Censored at date of last 
contact (Appendix 1.3)
Progression Free
Survival (PFS) 
Efficacy
Kaplan-Meier
Censored per Table A.1.3.1
(Appendix 1.3)
Overall Survival and 
PFS follow-up time) 
Efficacy
Reverse Kaplan-
Meier
Event and censor in the
original KM analysis are 
reversed.
 
8.2.3.4. DLT
A listing of the DLTs will be provided by arm and cohort.   
 
8.2.4. Safety Analyses 
All safety analyses will be summarized based on the safety analysis set. 
8.2.4.1. Adverse Events
Overall Summary of AEs  
An AE will be regarded as treatment-emergent, if
x
it occurs on the day of or after the first dose of either napabucasin or a combination drug 
and up to 30 days after the last dose of any study drug; or  
x
it occurs prior to first dose date of either napabucasin or a combination drug and worsens 
in severity on therapy and up to 30 days after the last dose of study drug. 
Adverse events will be coded by SOC and PT using the MedDRA version 18.0prior to the analysis.
The severity of AEs will be graded by the investigator using CTCAE Version 4.0. The 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: 


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 19
 
 
x
Patients with at least one TEAE 
x
Patients with TEAE of CTCAE Grade 3 or higher 
x
Patients with serious TEAE 
x
Patients with napabucasin related TEAE
x
Patients with napabucasin related TEAE of CTCAE Grade 3 or higher 
x
Patients with Cetuximab related TEAE
x
Patients with Cetuximab related TEAE of CTCAE Grade 3 or higher 
x
Patients with Panitumumab related TEAE
x
Patients with Panitumumab related TEAE of CTCAE Grade 3 or higher 
x
Patients with Capecitabine related TEAE
x
Patients with Capecitabine related TEAE of CTCAE Grade 3 or higher 
x
Patients with napabucasin related serious TEAE
x
Patients with napabucasin related serious TEAE of CTCAE Grade 3 or higher 
x
Patients with Cetuximab related serious TEAE
x
Patients with Cetuximab related serious TEAE of CTCAE Grade 3 or higher 
x
Patients with Panitumumab related serious TEAE
x
Patients with Panitumumab related serious TEAE of CTCAE Grade 3 or higher 
x
Patients with Capecitabine related serious TEAE
x
Patients with Capecitabine related serious TEAE of CTCAE Grade 3 or higher 
x
TEAE as the primary reason leading to end of study 
Summary of AEs by System Organ Class and Preferred Term 
The number and percentage of patients with AEs 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 grade will be presented in the descending order of frequency counts for all grades. 
Treatment Related TEAE
AEs reported with a relationship to a treatment considered by the investigator to be ‘possible’, 
‘probable’ or ‘definite’ will be considered “Related” to BBI608 or a combination drug,
respectively. Missing relationship will be considered as “Related”.  Summaries similar to those for 
the “all causality AEs” will be provided.   
Grade II or above Diarrhea
Number of days of Grade II or above diarrhea will be summarized. For patients who had a Grade 
II or above diarrhea TEAE ongoing at the time of analysis, the duration of TEAE will be censored 
at data cutoff or safety follow-up completion date, whichever is earlier. The safety follow-up 
completion date is the defined as the earlier day of the last treatment plus 30 days and death day 
(if applicable). 
Serious AE and Death


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 20
 
 
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.  
Deaths that occur on the same day or after the first dose of study treatment and within 30 days of 
the last dose of any study treatment will be summarized. The number and percentage of patients
who died during the study treatment and within 30 days after the last dose will be presented.   
A listing of death data will include all deaths that occurred during the reporting period for deaths, 
which starts from the signing of informed consent to the end of the follow-up period.  The listing 
will include date of death, and the number of days relative to the administration of the first and 
last dose.  
Adverse Events of Clinical Relevance
Selected AEs were pre-specified for additional focus due to the potential clinical significance of 
the event and/or the potential association with the investigational product.  These events include 
those in the standard MedDRA (narrow or broad, as noted) query terms of:  non-infectious diarrhea 
(broad SMQ), gastrointestinal haemorrhage (narrow SMQ), gastrointestinal obstruction (narrow 
SMQ),  acute kidney injury (narrow acute renal failure SMQ) and preferred term of ventricular 
fibrillation and ventricular tachycardia.  Tables listing the incidence, maximum severity and drug 
relationship of these events in the safety population will be generated. 
8.2.4.2. Laboratory Data 
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units.  If a laboratory value is reported using a non-numeric qualifier 
(eg, less than [<] a certain value, or greater than [>] a certain value), the given numeric value will 
be used in the summary statistics, ignoring the non-numeric qualifier. 
Laboratory test results will be summarized according to the scheduled sample collection time 
point.  Change from baseline will also be presented.  Unscheduled laboratory test results will be 
listed and included in laboratory shift tables.  The parameters to be analyzed follow: 
x
Hematology:  CBC including hemoglobin, hematocrit, white blood cell count with
5-part differential, red blood cell, and platelet count. 
x
Blood chemistry:  CO2, calcium, phosphorus, magnesium, albumin, glucose, serum 
creatinine, lactate dehydrogenase (LDH), uric acid, blood urea nitrogen (BUN), AST, 
ALT, alkaline phosphatase, total and direct bilirubin, and total protein, sodium, potassium,
and chloride.


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 21
 
 
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI CTCAE for 
toxicity (version 4.0) from baseline to post baseline worst CTC grade.  Parameters to be tabulated 
will include:
x
Hematology: ALC, ANC, hemoglobin, platelet count, WBC
x
Serum chemistry: ALT, AST, alkaline phosphatase, creatinine, total bilirubin, calcium, 
magnesium, potassium, sodium, and phosphate. 
Summary statistics will also be presented for shift from baseline urinalysis values.
x
Urinalysis: protein, specific gravity, glucose, and blood. 
By-patient listings to be presented include hematology, serum chemistry, and urinalysis results.
A listing of all laboratory parameters, including hematology, biochemistry, and urinalysis, will be 
provided, including the test result, units, normal range (H and L) and change from baseline, and 
CTCAE grades (if available).  Patients who developed toxicities of Grade  3 will also be listed. 
Figures of maximum post-baseline vs baseline values will be produced for key lab parameters, 
including but not limited to ANC, platelets, and liver function tests (ALT/SGPT, AST/SGOT, 
alkaline phosphatase, and total bilirubin) as well as E-DISH scatter plots. 
8.2.4.3. Electrocardiograms
12-lead ECG with categorical results (Normal, Abnormal [Not clinically significant], Abnormal 
[clinically significant]) will be summarized. Shift tables showing results from baseline to worst 
post baseline will be provided. A patient listing will also be provided. 
8.2.4.4. Vital Signs
For systolic blood pressure, diastolic blood pressure, pulse, and respiration summary statistics for 
baseline values and maximum change (maximum increase, maximum decrease and no change)
from baseline will be summarized based on the safety analysis set.
Summaries of markedly abnormal vital signs parameters, including blood pressure (BP) , pulse, 
and BMI,will be presented.  
Values for vital signs for all patients will be presented in a listing, and patients with markedly 
abnormal values will be flagged. 
Markedly abnormal ranges for vital signs parameters are given in the following table.


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 22
 
 
Table Vital Sign Threshold of Interest
Vital Sign 
Parameter 
Markedly Abnormal (Low) 
Markedly Abnormal (High) 
Systolic BP 
ďƐŽůƵƚĞǀĂůƵĞчϵϬŵŵ,Ő͕ŽƌĂ
decrease from baseline ı20 mmHg 
ďƐŽůƵƚĞǀĂůƵĞшϭϴϬŵŵ,Ő͕ŽƌĂŶ
increase from baseline ı20 mmHg 
Diastolic BP 
ďƐŽůƵƚĞǀĂůƵĞчϱϬŵŵ,Ő͕ŽƌĂ
decrease from baseline ı15 mmHg 
ďƐŽůƵƚĞǀĂůƵĞшϭϬϱŵŵ,Ő͕ŽƌĂŶ
increase from baseline ı 15 mmHg 
Pulse 
ďƐŽůƵƚĞǀĂůƵĞчϱϬďƉŵ 
ďƐŽůƵƚĞǀĂůƵĞшϭϮϬďƉŵ 
BMI 
ďƐŽůƵƚĞǀĂůƵĞчϭϴŬŐͬŵ2 
ďƐŽůƵƚĞǀĂůƵĞшϮϱŬŐͬŵ2 
9. REFERENCES 
[1] Clopper, C. J. and Pearson, E. S., 1934. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika, 26, 404–413.
[2] Brookmeyer, R. and Crowley, J., 1982. A confidence interval for the median survival time. Biometrics,
pp.29-41.
[3] Kaplan, E.L. and Meier, P., 1958. Nonparametric estimation from incomplete observations. Journal of 
the American statistical association, 53(282), pp.457-481.
[4] Kalbfleisch, J.D. and Prentice, R.L., 1980. Statistical analysis of failure time data.
[5] Boston Biomedical, Inc, 2014. A Phase II Clinical Study of BBI608 Adult Patients with Advanced 
Colorectal Cancer. Amendment 2
[6] Schemper and Smith.  A note on quantify follow-up in studies of Failure time. Controlled Clinical Trials, 
17:343-346 (1996)


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 23
 
 
10. APPENDICES 
Appendix 1.1. 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 
 
Patients with an imaging assessment that meets criteria for either complete response (CR) or 
partial response (PR) must have a repeat radiologic assessment approximately 4 weeks after the 
assessment in which CR or PR criteria were met.


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 24
 
 
Appendix 1.2. Evaluation of Best 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
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
The best overall response (BOR) is the best response recorded from start date until disease 
progression or start of new anti-cancer therapy.  BOR is determined by the following order.   
CR:  One objective status of CR documented before progression and start of new anti-cancer 
therapy.  
PR:  One objective status of PR documented before progression and start of new anti-cancer 
therapy, but not qualifying as CR. 
SD: At least one objective status of SD documented at least (8 weeks – 1 days) after start date 
and before progression and the start of new anti-cancer therapy but not qualifying as CR or PR.   
PD:  Progression documented within (16 weeks + 1 days) after start date and not qualifying as 
uCR, uPR, or SD.   
NE:  All other cases.  Note that reasons for NE should be summarized and the following reasons 
could be used:  
x
Early death (Note: death prior to (8 weeks – 1 days) after start date)
x
No post-baseline assessments 
x
All post-baseline assessments have overall response of NE
x
New anti-cancer therapy started before first post-baseline assessment
x
SD too early (< (8 weeks – 1 days) after start date)
x
PD too late (> (16 weeks + 1 days) after start date)


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 25
 
 
Special and rare cases where BOR is NE due to both early SD and late PD will be 
classified as ‘SD too early’.
Appendix 1.3. Censoring for Time to Event Data 
Table A.1.3.1 summarizes the censoring rules for the PFS analysis and displays censoring 
hierarchy for this study. Table A.1.3.2 shows the general reasons for PFS censoring and where 
the censoring hierarchy in Table A.1.3.1 came from. 
     Table A.1.3.1 PFS Censoring Reasons and 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 and no 
tumor progression
Date of previous adequate 
radiological assessment 
immediately prior to start 
of new therapy
Censored
3
Tumor progression (per RECIST 1.1) 
documented after 2 scan intervals 
following previous adequate radiological 
tumor assessment
Date of previous adequate 
radiological assessment
Censored
4, 5
No tumor progression (per RECIST 1.1) 
and patient lost to follow-up or withdrawal 
of consent
Date of last adequate 
radiological Assessment
Censored
6
No post baseline radiological tumor 
assessment available and no death reported 
within 2 scan intervals following the date 
of the first dose of study drug 
(napabucasin) 
Date of First Dose 
Censored
No post baseline radiological tumor 
assessment available but death reported 
within 2 scan intervals following the date 
of the first dose of study drug 
(napabucasin) 
Date of Death
Event
7
No tumor progression (per RECIST 1.1) 
and no death reported within 2 scan 
intervals following last adequate 
radiological tumor assessment
Date of last adequate 
radiological tumor 
assessment 
Censored
No tumor progression (per RECIST 1.1) 
but death reported within 2 scan intervals 
Date of death
Event


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 26
 
 
following last adequate radiological tumor 
assessment 
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 (ie, 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.
Table A.1.3.2 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+1 day) from last adequate post-
baseline tumor assessment/start date
Event after missing assessments a
4
1RHYHQWDQG>ZLWKGUDZDORIFRQVHQWGDWHVWDUWGDWH25
End of study (EOS) = Patient refused further FU] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any 
EPOCH after screening says patient will not continue into 
any subsequent phase of the study] 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+1 day) after last adequate tumor assessment.   <Note: This should correspond to 2 or more 
missing assessments using the nominal schedule of assessments but best to describe directly as 16 weeks to match on 
how the analyses are performed as per the table above>
Date of Last Contact for Overall Survival 
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 (eg, blood draws [laboratory, PK], vital signs, performance 
status, ECG, tumor assessments, concomitant radiation, surgery)   


Protocol <BBI608-224> 
Statistical Analysis Plan
Sumitomo Dainippon Pharma Oncology CONFIDENTIAL
Page 27
 
 
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/enrollment date
x
Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up or death). 
Note: 
x
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 (eg, the 
date a blood sample was processed) should not be used.  
x
Assessment dates after the cutoff date will not be applied to derive the last contact date.