Clinical trial NCT02279719
Conditions: Hepatocellular Carcinoma
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2014-12-01; Completion date: 2019-10-01
Enrollment: 97 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open label, three-arm, phase 1 dose escalation study and phase 2 study of BBI608 in combination with sorafenib, or BBI503 in combination with sorafenib. The study population is adult patients with advanced hepatocellular carcinoma who have not received systemic chemotherapy.

Detailed description:
This is an open label, three-arm, phase 1 dose escalation study and phase 2 study of BBI608 in combination with sorafenib, or BBI503 in combination with sorafenib. The study population is adult patients with advanced hepatocellular carcinoma (HCC) who have not received systemic chemotherapy.

The phase 1 portion will involve dose-escalation of BBI608 administered in combination with a fixed starting dose of sorafenib (Arm 1), and dose escalation of BBI503 administered in combination with a fixed starting dose of sorafenib (Arm 2). The fixed starting dose-level of sorafenib for both arms will be 400 mg twice daily (800 mg total daily dose). Eligible patients will be randomized to either Arm 1 or Arm 2.

The phase 2 portion will be an open-label, 3-arm, randomized trial of patients with advanced HCC who have not received prior systemic treatment. Patients will be randomized to receive either, Arm 1: sorafenib administered in combination with BBI608 (at the RP2D determined for BBI608 plus sorafenib during the phase 1 portion); Arm 2: sorafenib in combination with BBI503 (at the RP2D determined for BBI503 plus sorafenib during the phase 1 portion), or Arm 3: sorafenib alone at a starting dose of 400 mg twice daily. The starting dose for sorafenib is the same for all study arms.

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: BBI608 intervention 2: BBI503 intervention 3: Sorafenib
Intervention descriptions: intervention 1: BBI608 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. intervention 2: BBI503 will be administered in combination with sorafenib at the RP2D determined during the phase 1 dose-escalation portion of study. intervention 3: Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose). Sorafenib should be taken on an empty stomach, one hour prior to or two hours after meals. Sorafenib should not be taken with study drug, and at least 2 hours should separate a dose of sorafenib from a dose of study drug.

Protocol documents:
Prot_000.pdf: 
 
 
Confidential 
 
Page: 1 
 
  
 
TITLE: 
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Sorafenib or BBI503 in Combination with 
Sorafenib in Adult Patients with Hepatocellular 
Carcinoma 
PROTOCOL NUMBER: 
BBI608-503-103HCC 
STUDY DRUGS: 
BBI503 
BBI608 
SPONSOR: 
 
 
 
 
 
MEDICAL MONITOR: 
 
 
SAFETY FAX: 
(
  
SAFETY CONTACT: 
  
DATE OF PROTOCOL: 
September 12, 2014 
DATE OF AMENDMENT: 
  April 3, 2018 
AMENDMENT: 
4 
 
 
 
 


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SYNOPSIS 
Study Title: 
A Phase Ib/II Clinical Study of BBI608 in Combination with 
Sorafenib, or BBI503 in Combination with Sorafenib in Adult 
Patients with Hepatocellular Carcinoma  
Study Number: 
BBI608-503-103HCC 
Study Phase:  
Phase Ib/II 
Study Drugs: 
BBI608 and BBI503, investigational, small molecule, anticancer drugs that are 
hypothesized to affect multiple oncogenic pathways, including pathways 
implicated in cancer stem cell viability.  
Primary Objectives:  
Phase Ib: 
To determine the safety, tolerability, and recommended Phase II dose (RP2D) 
of BBI608 administered in combination with sorafenib and of BBI503 
administered in combination with sorafenib in adult patients with advanced 
hepatocellular carcinoma who have not received prior systemic chemotherapy. 
Phase II: 
To evaluate the tolerability, safety. and preliminary anti-tumor activity in 
patients with advanced hepatocellular carcinoma randomized to receive 
treatment with sorafenib in combination with BBI608, sorafenib in combination 
with BBI503, or sorafenib alone; BBI608 and BBI503 would be administered 
at their respective RP2D dose levels for combination administration with 
sorafenib, which were determined during phase Ib. 
Secondary 
Objectives: 
To determine the pharmacokinetic profile of BBI608 administered in 
combination with sorafenib and of BBI503 administered in combination with 
sorafenib. 
To perform biomarker studies for BBI608 administered in combination with 
sorafenib and for BBI503 administered in combination with sorafenib. 
Study Design: 
 
This is an open label, phase Ib/II study.  The study population is adult patients 
with advanced hepatocellular carcinoma who have not received systemic 
chemotherapy.   
The phase Ib portion will involve dose-escalation of BBI608 administered in 
combination with a fixed starting dose of sorafenib (Arm 1), and dose escalation 
of BBI503 administered in combination with a fixed starting dose of sorafenib 
(Arm 2).  The fixed starting dose-level of sorafenib for both arms will be 400 
mg twice daily (800 mg total daily dose).  Eligible patients will be randomized 
to either Arm 1 or Arm 2.   
In Arm 1, escalating doses of BBI608 will be administered to cohorts of three 
to six patients until RP2D is determined according to the criteria for determining 
dose-limiting toxicity (DLT) and the criteria for dose-escalation.  
In Arm 2, escalating doses of BBI503 will be administered to cohorts of three 
to six patients until RP2D is determined according to the criteria for determining 
dose-limiting toxicity (DLT) and the criteria for dose-escalation.   
Prior to initiation of combination therapy in each arm, sorafenib will be 
administered as monotherapy starting on Cycle 1, Day 1 for 14 days.  Dose-
adjustment of sorafenib according to the approved product label is allowed.  
Following the sorafenib run-in period, the combination regimen will begin on 
Cycle 1, Day 15.  Protocol therapy will continue in repeating 28-day cycles until 
disease progression, unacceptable toxicity, or another discontinuation criterion 


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is met.   
For both arms, pharmacokinetic (PK) studies will be performed on Cycle 1, Day 
15 and Cycle 2, Day 15.  An additional pharmacokinetic study may be 
performed to confirm exposure following dose-modification.  Once RP2D is 
determined for both study arms, the phase II portion will begin.   
The phase II portion will be an open-label, 3-arm, randomized phase II trial of 
patients with advanced HCC who have not received prior systemic treatment.  
Patients will be randomized to receive either, Arm 1: sorafenib administered in 
combination with BBI608 (at the RP2D determined for BBI608 plus sorafenib 
during the phase Ib portion); Arm 2: sorafenib in combination with BBI503 (at 
the RP2D determined for BBI503 plus sorafenib during the phase Ib portion), 
or Arm 3: sorafenib alone at a starting dose of 400 mg twice daily.  The starting 
dose for sorafenib is the same for all study arms.  
Note: 
Once the amendment 3 is in effect, Arm 2 in the Phase II portion will be closed 
for enrollment due to BBI503 portfolio priorities and to increase efforts in 
enrolling patients on to Arms 1 and 3. 
At the time of the amendment 3 being in effect, there were approximately 10 
subjects already enrolled in Arm 2.  Therefore, the actual sample size in Phase 
II in the end is projected to be approximately 70 patients after the amendment 3 
Pharmacodynamic assessments will be performed in patients with readily 
accessible tumors through an optional on-study tumor biopsy.  Archival tissue, 
if available, will be collected from all patients.  
Throughout the study, safety and tolerability of BBI608 in combination with 
sorafenib and of BBI503 in combination with sorafenib will be assessed for the 
duration of study treatment and up to 30 days after discontinuation of study drug 
(either BBI608 or BBI503).   
Evaluation of anti-tumor activity will be performed at regular 8–week intervals, 
with the first assessment 8 weeks (56-days) after Cycle 1, Day 1.  The radiologic 
assessments will be evaluated according to RECIST 1.1 and modified RECIST 
(mRECIST) for patients with HCC.  Alpha-feto protein (AFP) measurement 
will be performed at baseline, at the end of the 2-week sorafenib monotherapy 
Run-In, and at the start of each subsequent study cycle.   
A patient may continue protocol therapy beyond progression that is determined 
by RECIST criteria (either RECIST 1.1 or mRECIST for patients with HCC), 
provided that the patient is obtaining potential clinical benefit in the opinion of 
the investigator.  If sorafenib is discontinued due to sorafenib-related toxicities, 
study drug (either BBI608 or BBI503) may be continued.   
Study Population:  
 
This study will enroll patients with advanced hepatocellular carcinoma (HCC) 
arising from any setting who have not received prior systemic chemotherapy for 
their disease, and for which sorafenib is an appropriate treatment option in the 
judgment of the treating investigator.   
Prior surgical or loco-regional therapy is allowed, including trans-catheter 
arterial embolization, trans-catheter arterial chemoembolization, percutaneous 
ethanol injection, or radiofrequency ablation, provided that the procedure was 
performed at least 4 weeks prior to Cycle 1, Day 1, and provided that there has 
been documented disease progression per RECIST (either RECIST 1.1 or 
mRECIST for patients with HCC) since the surgical procedure.    


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Additional key inclusion criteria include: ECOG performance status < 1, Child-
Pugh class A and B7 albumin, adequate renal function, and a life expectancy of 
greater than 3 months.  Patient accrual will occur over a period of time 
dependent upon the enrollment rate of the study.  Patients with HIV infection 
are excluded. 
Test Product, Dose, 
and Mode of 
Administration:  
 
Phase Ib: 
Patients in this trial will receive study drug in combination with a fixed dose of 
sorafenib according to the arm they are randomly assigned to and according to 
the dose-level cohort that is currently open.  
Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg 
total daily dose).  This dose of sorafenib will be the same for each arm and for 
each dose-level cohort.  Sorafenib should be taken on an empty stomach, one 
hour prior to or two hours after meals.  Sorafenib should not be taken with study 
drug, and at least 2 hours should separate a dose of sorafenib from a dose of 
study drug. 
The starting dose of study drug (BBI608 or BBI503) and dosing instructions for 
each arm during the phase are as follows. 
Arm 1: 
BBI608 will be administered orally, twice daily, with approximately 12 hours 
between doses.  The first dose of BBI608 should be administered shortly after 
waking in the morning.  The second dose of BBI608 should be taken in the 
evening.  BBI608 should be taken with fluids, either 1 hour before a meal or 2 
hours after.  The first dose of BBI608 should be taken prior to the first dose of 
sorafenib.   
The dose of BBI608 to be administered will depend on the assigned dose-level 
cohort as follows in the table below: 
BBI608 Dose Level 
BBI608 Dose & Schedule 
BBI608 Dose-Level I 
160 mg Twice Daily 
BBI608 Dose-Level II 
240 mg Twice Daily 
Initially, 3 patients will be enrolled at BBI608 Dose-Level 1.  Dose-escalation 
will proceed according to the Criteria for Dose Escalation and Criteria for 
Determination of Dose-Limiting Toxicity (DLT).  
Alternate and/or intermediate dose-levels are permitted upon agreement with 
the Principal Investigator and medical monitor for the Sponsor.  
Arm 2: 
BBI503 will be administered orally, daily. The daily dose of BBI503 will be 
administered before bed.  The dose of BBI503 to be administered will depend 
on the assigned dose-level cohort as follows in the table below: 
BBI503 Dose Level 
BBI503 Dose & Schedule 
BBI503 Dose-Level I 
100 mg Once Daily 
BBI503 Dose-Level II 
200 mg Once Daily 
Initially, 3 patients will be enrolled at BBI503 Dose-Level 1.  Dose-escalation 
will proceed according to the Criteria for Dose Escalation and Criteria for 
Determination of Dose-Limiting Toxicity (DLT).   
Intermediate dose-levels are permitted upon agreement with the Principal 
Investigator and medical monitor for the Sponsor.  The total daily dose of 
BBI503 may be divided into sub-doses. 


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Phase II Portion: 
The dose of BBI608 or BBI503 *to be administered in combination with 
sorafenib during the phase II portion will be the RP2D determined during the 
phase Ib dose-escalation portion of study.  Sorafenib administration will be as 
described for the phase Ib portion.   
* Once the amendment 3 is in effect, Arm 2 in Phase II portion will be closed 
for enrollment 
Criteria for Dose 
Escalation – Phase 
Ib Portion Only 
Enrollment at the next dose level and/or additional patients into the ongoing 
cohort will occur according to the following criteria: 
• 
If zero treated patients experience a DLT (defined below) by Day 28 of 
continuous daily dosing, then dose escalation will occur. 
• 
If one treated patient experiences a DLT (defined below) by Day 28 of 
continuous daily dosing, then an additional three patients will be enrolled 
for a total of six patients treated at the same dose level.  Escalation will 
occur if no additional DLTs are seen in that cohort (one of six patients). 
• 
If two or more treated patients at a dose level experience a DLT by Day 
28 of continuous daily dosing, this will be the maximally administered 
dose.     
• 
A total of six patients will be treated at the previous dose level, and 
subsequent escalation will not exceed the maximally administered dose.   
The maximally tolerated dose (MTD) is defined as the dose level at which no 
more than one out of six patients have an observable DLT.  RP2D will be 
determined according to safety, tolerability, and pharmacokinetics.  The criteria 
for dose-escalation will apply to a given administration schedule independently. 
Criteria for 
Determination of 
Dose-Limiting 
Toxicity: 
 
Dose-Limiting Toxicity (DLT) is defined as the occurrence of any of the 
following toxicities possibly, probably, or definitely related to study drug (either 
BBI608 or BBI503) or to study drug in combination with sorafenib during the 
first 28 days of combination therapy, unless there is a clear alternative 
explanation:   
• 
CTCAE (Common Terminology Criteria for Adverse Events) Grade 4 
hematological toxicity. 
• 
Grade 3 thrombocytopenia in the presence of active bleeding will be 
considered a DLT. 
• 
Grade 3 or 4 non-hematological toxicity, except for Grade 3 
nausea/vomiting/anorexia, diarrhea, or fatigue, symptoms that will be 
considered DLTs only if they persist more than seven (7) days despite 
optimal medical management.  Grade 4 toxicity will be considered DLT. 
Alopecia will not be considered DLT.  Assessment for DLT will occur during 
the first 28 days of BBI608 or BBI503 therapy in combination with sorafenib.  
DLT will be determined from adverse events, as well as changes from baseline 
in physical examination findings and laboratory parameters.   
The criteria for determination of DLT will apply to a given administration 
schedule independently.  Patients who discontinue protocol therapy for a reason 
other than DLT may be replaced in order to fully evaluate a given dose-level.   
Duration of 
Treatment:  
For an individual patient, treatment with study drug (either BBI608 or BBI503) 
and sorafenib will continue in 28-day cycles or until the investigator determines 
the patient is no longer deriving potential clinical benefit due to unacceptable 
toxicity, disease progression, or another discontinuation criterion.   
A patient may continue protocol therapy beyond progression that is determined 


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solely by RECIST 1.1 criteria or mRECIST criteria for patients with HCC, 
provided that the patient is obtaining potential clinical benefit in the opinion of 
the investigator. 
It is expected that most patients will receive between 4 and 24 weeks of 
treatment.  
Pharmacokinetic 
and 
Pharmacodynamic 
Variables: 
Pharmacokinetic variables to be determined include maximum plasma drug 
concentration (Cmax), time to reach Cmax (Tmax), area under the time-
concentration curve (AUC), and terminal half-life.   
Blood samples for PK analyses will be performed on Cycle 1, Days 15-16 and 
on Cycle 2, Day 15 of the phase Ib portion.  During the phase II portion, 
approximately six patients will collect PK as Phase I schedule, then a single 
pharmacokinetic blood draw may be obtained on Cycle 2, Day 15.    
Paraffin embedded tumor tissue is requested from all patients prior to initiation 
of protocol therapy.  Patients may enroll if they do not have archival tissue.  
Patients may enroll if they are not aware if they have archival tissue.   
Pharmacodynamic studies as well as the concentration of study drug (either 
BBI608 or BBI503) in tumors will be examined following study drug 
administration in patients with accessible tumors who consent to an optional on-
study biopsy. This optional biopsy will be obtained on Cycle 2, Day 15.   
Statistical Methods:  
 
Statistics will be descriptive in nature, and formal sample size calculations were 
not performed.     
Phase Ib: 
Central randomization will be performed whereby patients will be assigned to 
Arm 1 (BBI608 plus sorafenib) or Arm 2 (BBI503 plus sorafenib) using block 
randomization.  Each block will be considered a cohort with 3 subjects on Arm 
1 and 3 subjects on Arm 2.  After the first cohort for an Arm is complete, the 
dose level for the next cohort will be determined by the dose escalation rules.  
Safety will be summarized according to study arm.  All patients receiving at 
least one dose of study drug (either BBI608 or BBI503) will be considered 
evaluable for safety analyses.  Adverse events will be assessed according to 
CTCAE and will be evaluated by grade and organ class.  Adverse event listings 
and tabulated summaries of categorized adverse events will be generated for all 
patients.  Vital signs, laboratory data, and ECG data will be summarized for 
changes over time on study.   
The pharmacokinetic population will be all treated patients in a given arm with 
sufficient data to determine pharmacokinetic parameters.   
Phase II: 
Approximately 90 patients (30/arm) were planned to be randomized in 1:1:1 
ratio into three treatment arms: Arm 1 (sorafenib plus BBI608), Arm 2 
(sorafenib plus BBI503), and Arm 3 (sorafenib alone) before Amendment 3 was 
in effect.  After amendment 3 was in effect, Arm 2 in the Phase II portion was 
closed for enrollment and randomization is conducted in a 1:1 ratio to the two 
remaining arms: Arm 1 and Arm 3. The targeted sample size remains 30 for 
Arm 1 and 30 Arm 3 after the amendment 3. There were approximately 10 
subjects already enrolled in Arm 2 by the time amendment 3 was put into effect.  
Therefore, the total sample size of Phase II at the end of the trial is projected to 
be approximately 70 patients.  
Baseline characteristics as well as the observed safety, tolerability, and 
preliminary signs of anti-tumor activity will be summarized for each arm.   


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 The anti-tumor activity will be evaluated on an exploratory basis and will be 
summarized using descriptive statistics or graphics. Patient response will be 
assessed based on standard RECIST 1.1, as well as mRECIST for patients with 
HCC.  Data listings and summaries of tumor markers, imaging results, and 
similar data may be generated.  Kaplan-Meier estimates of overall survival and 
progression-free survival will be generated.  
Phase Ib and Phase II: 
 
Anti-tumor activity will be summarized by arm.  Patients in a given study arm 
who have received at least one cycle of study drug (either BBI608 or BBI503) 
and who have had at least one disease assessment following the initiation of 
therapy will be considered evaluable for response. 
The anti-tumor activity will be evaluated on an exploratory basis and will be 
summarized using descriptive statistics or graphics. Patient response will be 
assessed based on standard RECIST 1.1, as well as mRECIST for patients with 
HCC.  Data listings and summaries of tumor markers, imaging results, and 
similar data may be generated.  Kaplan-Meier estimates of overall survival and 
progression-free survival will be generated. 
 
Phase II 
There is no statistical hypothesis testing in the Phase 2 part and the sample size 
of Phase 2 part is considered to be clinically adequate to assess tolerability, 
safety, and preliminary anti-cancer activity of the study drugs of interest. 
Estimation and 95% confidence intervals will be provided for the proportion of 
patients with grade 3 adverse events by treatment, as well as for the proportion 
of patients that are alive and progression free 4 months (PFS-4) after 
randomization for each arm. 
 
 
 
 


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DOSE ESCALATION SCHEME BBI608-503-103HCC: A PHASE IB/II CLINICAL 
TRIAL 
 
Arm 1: BBI608 in Combination with Sorafenib 
Cohort 
No. 
Subjects 
Dose 
Level 
Dose & Schedule of  
BBI608 
I  
3* 
Level 1 
160 mg Twice Daily 
II 
3* 
Level 2 
240 mg Twice Daily 
*Group may be expanded to six subjects, as provided for in the protocol. 
 
 
Arm 2: BBI503 in Combination with Sorafenib 
Cohort 
No. 
Subjects 
Dose 
Level 
Dose & Schedule of 
BBI503 
I  
3* 
Level 1 
100 mg Daily 
II 
3* 
Level 2 
200 mg Daily 
 *Group may be expanded to six subjects, as provided for in the protocol. 
 
 
 
 
 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
DOSE ESCALATION SCHEME BBI608-503-103HCC: A PHASE IB/II CLINICAL TRIAL8 
1 
PRECLINICAL SUMMARY AND STUDY RATIONALE ..........................................16 
1.1 
Brief Scientific Background ..................................................................................16 
1.1.1 
BBI608 .........................................................................................................16 
1.1.2 
BBI503 .........................................................................................................16 
1.2 
Preclinical Efficacy ................................................................................................16 
1.2.1 
BBI608 .........................................................................................................16 
1.2.2 
BBI503 .........................................................................................................17 
1.3 
Safety and Encouraging Signs of Antitumor Activity in Phase I ..........................18 
1.3.1 
BBI608 .........................................................................................................18 
1.3.2 
BBI503 .........................................................................................................19 
1.4 
Combination Therapy for Hepatocellular Carcinoma ............................................19 
2 
STUDY OBJECTIVES ....................................................................................................21 
2.1 
Primary Objective ..................................................................................................21 
2.2 
Secondary Objectives.............................................................................................21 
3 
SELECTION OF STUDY POPULATION .....................................................................22 
3.1 
Inclusion Criteria ...................................................................................................22 
3.2 
Exclusion Criteria ..................................................................................................23 
3.3 
Number of Patients ................................................................................................24 
4 
INVESTIGATIONAL PLAN ..........................................................................................25 
4.1 
Overall Study Design .............................................................................................25 
4.2 
Design - Phase Ib ...................................................................................................25 
4.3 
Design – Phase II ...................................................................................................28 
5 
STUDY VISITS ...............................................................................................................32 
5.1 
Overview ................................................................................................................32 
5.2 
Informed Consent...................................................................................................32 
5.3 
Pre-Study Evaluations (Baseline) ..........................................................................33 
5.4 
On-Study Evaluation & Assessment Schedule │ Cycle 1 .....................................33 
5.4.1 
Cycle 1, Day 1 │ Start of Sorafenib Run-In ................................................34 
5.4.2 
Cycle 1, Day 8 │ Mid Run-In (Phone Call is allowed) ...............................34 
5.4.3 
Cycle 1, Day 15 │Start of Combination Therapy .......................................34 
5.4.4 
Cycle 1, Day 16 │ Phase Ib Arm 2 Only .....................................................35 
5.4.5 
Cycle 1, Day 22 ...........................................................................................35 
5.5 
On-Study Evaluation & Assessment Schedule │ Cycle 2 .....................................35 
5.5.1 
Cycle 2, Day 1 .............................................................................................35 
5.5.2 
Cycle 2, Day 15 ...........................................................................................35 
5.6 
On-Study Evaluation & Assessment Schedule │ Cycle 3 and Subsequent Cycles36 
5.6.1 
Cycle 3, Day 1 (and Day 1 of all subsequent study cycles) .........................36 
5.6.2 
Cycle 3, Day 15 (and Day 15 of all subsequent cycles)* ............................36 
5.7 
Tumor Evaluation Visits ........................................................................................36 
5.7.1 
Baseline ........................................................................................................36 
5.7.2 
Per-Protocol .................................................................................................37 
5.8 
End of Study Evaluation ........................................................................................38 
5.9 
Discontinuation from Study ...................................................................................38 


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5.10 
Follow Up After Treatment Discontinuation .........................................................39 
6 
STUDY PROCEDURES .................................................................................................41 
6.1 
Medical History .....................................................................................................41 
6.2 
Physical Examination.............................................................................................41 
6.3 
Clinical Laboratory Tests .......................................................................................41 
6.4 
Pharmacokinetic Assessments ...............................................................................42 
6.4.1 
Phase Ib ........................................................................................................42 
6.4.1.1 
Arm 1: BBI608 ..................................................................................42 
6.4.1.2 
Arm 2: BBI503 ..................................................................................43 
6.4.2 
Phase II ........................................................................................................43 
6.5 
Pharmacodynamic Assessments ............................................................................44 
6.5.1 
Archival Tissue ............................................................................................44 
6.5.2 
Tumor Biopsy ..............................................................................................45 
7 
TREATMENT .................................................................................................................46 
7.1 
Sorafenib ................................................................................................................46 
7.2 
Study Drug .............................................................................................................46 
7.2.1 
BBI608 .........................................................................................................46 
7.2.1.1 
BBI608 Administration ......................................................................46 
7.2.2 
BBI503 .........................................................................................................47 
7.2.2.1 
BBI503 Administration ......................................................................47 
7.2.3 
Investigational Product Accountability .......................................................47 
7.3 
Dose Modifications ................................................................................................47 
7.3.1 
Sorafenib ......................................................................................................47 
7.3.2 
Study Drug – BBI608 or BBI503 ................................................................48 
7.3.2.1 
Specific Pharmacologic Recommendations - BBI608 and BBI503 ..49 
7.4 
Treatment Compliance ...........................................................................................50 
7.5 
Blinding..................................................................................................................51 
7.6 
Prior Treatment ......................................................................................................51 
7.7 
Concomitant Medication ........................................................................................51 
7.7.1 
Permitted Treatment ....................................................................................51 
7.7.2 
Prohibited Treatment ...................................................................................51 
7.7.3 
Drug-Drug Interactions ................................................................................52 
7.7.3.1 
BBI608 ...............................................................................................52 
7.7.3.2 
BBI503 ...............................................................................................52 
7.7.3.3 
Sorafenib ............................................................................................52 
8 
SAFETY ASSESSMENTS ..............................................................................................54 
8.1 
Adverse Events ......................................................................................................54 
8.1.1 
Assessments .................................................................................................54 
8.1.2 
Definitions ...................................................................................................54 
8.2 
Serious Adverse Events .........................................................................................55 
8.2.1 
Definitions ...................................................................................................55 
8.2.2 
Reporting Serious Adverse Events ..............................................................55 
9 
ASSESSMENT OF ANTI-TUMOR ACTIVITY ............................................................56 
9.1 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ..............................56 
9.1.1 
Basic Definitions for RECIST 1.1 ...............................................................56 
9.1.2 
RECIST 1.1 Methods of Measurement ........................................................57 


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9.1.3 
RECIST 1.1 Baseline Documentation of “Target” and “Non-Target” Lesions 57 
9.1.4 
Response Criteria and Classification for RECIST 1.1 .................................57 
9.1.5 
Evaluation of Overall Response for RECIST 1.1 ........................................58 
9.2 
Modified RECIST Assessment for Hepatocellular Carcinoma (mRECIST) .........59 
9.2.1 
Basic Definitions for mRECIST ..................................................................59 
9.2.2 
Image Acquisition for mRECIST ................................................................59 
9.2.3 
Response Criteria and Classification for mRECIST ....................................59 
9.2.4 
Evaluation of Overall Response in mRECIST ............................................60 
9.3 
Assessment of New Lesions ..................................................................................61 
9.3.1 
New Lesions in RECIST 1.1 ........................................................................61 
9.3.2 
New Lesions in mRECIST for HCC ............................................................61 
10 PLANNED STATISTICAL METHODS ........................................................................62 
10.1 
Analysis Populations ..............................................................................................62 
10.2 
Phase Ib Randomization ........................................................................................62 
10.3 
Phase II Randomization .........................................................................................63 
10.4 
Primary and Secondary Study Objectives ..............................................................63 
10.4.1 
Primary Objectives ......................................................................................63 
10.4.2 
Secondary Objectives ..................................................................................63 
10.5 
Determination of Sample Size ...............................................................................64 
10.6 
Safety Analysis ......................................................................................................64 
10.7 
Pharmacokinetics, Pharmacodynamics and Exposure-Response Variables ..........65 
11 QUALITY CONTROL AND ASSURANCE .................................................................66 
11.1 
Compliance with the Protocol ................................................................................66 
11.2 
Registration and Enrollment ..................................................................................66 
11.3 
Removal, Replacement, or Early Withdrawals of Subjects ...................................66 
12 GCP COMPLIANCE AND ETHICAL CONSIDERATIONS .......................................67 
12.1 
Institutional Review Board ....................................................................................67 
12.2 
Compliance with Good Clinical Practice and Ethical Considerations ...................67 
12.3 
Informed Consent and Permission to Use Private Health Information ..................67 
13 STUDY MANAGEMENT ..............................................................................................69 
13.1 
Amendments to the Protocol ..................................................................................69 
13.2 
Investigator Brochure and Information Materials ..................................................69 
13.3 
Pre-investigational Documents ..............................................................................69 
13.4 
Drug Inventory Record ..........................................................................................69 
13.5 
Disposition of Used and Unused Study Drug ........................................................70 
13.6 
Study Records ........................................................................................................70 
13.7 
Record Retention ...................................................................................................70 
13.8 
Subject Confidentiality ..........................................................................................70 
13.9 
Monitoring .............................................................................................................70 
13.10 Case Report Form (CRF) Completion ...................................................................70 
13.11 Final Site Report ....................................................................................................71 
13.12 Final Study Report .................................................................................................71 
13.13 Use of Information .................................................................................................71 
13.14 Publication .............................................................................................................71 
13.15 Research Outside the Terms of this Protocol .........................................................72 
14 APPENDIX A:  SCHEDULE OF ASSESSMENTS - PHASE IB ..................................73 


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15 APPENDIX B:  SCHEDULE OF ASSESSMENTS - PHASE II ....................................74 
16 APPENDIX C:  PERFORMANCE STATUS .................................................................76 
17 SPONSOR SIGNATURE ................................................................................................77 
18 INVESTIGATOR’S SIGNATURE .................................................................................78 
19 REFERENCES ................................................................................................................79 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


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GCS-F 
Granulocyte Colony Stimulating Factor 
GGT 
Gamma Glutamyl Transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
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 


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PR 
Partial Response 
QD 
Once Daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
RBC 
Red Blood Cell (count) 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SE 
Standard Error  
SGOT 
Serum Glutamic Oxaloacetic Transaminase (AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (ALT) 
Tmax 
Time to Maximum Plasma Concentration 
TNM Scale 
Tumor Node Metastases Scale 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell (count) 


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1 PRECLINICAL SUMMARY AND STUDY RATIONALE  
1.1 
Brief Scientific Background 
Recent studies have uncovered the presence of cancer stem cells (CSCs, 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 for cancer 
patients is being explored (Clevers, 2011: Singh and Settleman, 2010; Lobo, Shimono et al. 2007; Boman 
and Wicha, 2008; please also find a list of reviews on CSCs 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)). 
This study will evaluate the safety, tolerability, and preliminary signs of activity of two different 
investigational agents designed as cancer stem cell inhibitors, BBI608 and BBI503, each administered in 
combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).  Sorafenib is an 
oral agent currently approved for the treatment of advanced HCC.  A combination regimen which targets 
the cancer stem cell population in addition to the bulk tumor cells (non-stem cancer cells) may be an 
approach for this disease.   
The study agents, BBI608 and BBI503, are discussed subsequently.  Brief introductions to both agents are 
followed by pre-clinical efficacy data and updates from clinical development to date.  Additional 
information is available in the Investigator Brochures (IB) for both compounds.   
1.1.1 BBI608 
BBI608 is a small molecule that is hypothesized to affect multiple oncogenic cellular pathways, including 
inhibition of the STAT3 pathway, which has been implicated in cancer stem cell viability.  
1.1.2 BBI503 
BBI503 is the product candidate selected from our BBI5600 program designed by BBI to target CSCs. 
BBI503 may target cancer through inhibition of kinases that may be responsible for cancer stemness 
properties.  
1.2 
Preclinical Efficacy 
1.2.1 BBI608 
Cancer stem cells are intrinsically resistant (more than 5 to 10-fold than other tumor cells) to 
chemotherapeutic drugs. BBI608 has activity (~100 to 500 nM) against cancer stem cells in vitro.  At the 
same time, BBI608 spares normal hematopoietic stem cells (IC50 not reached at 30 μM) in vitro.  
BBI608 has demonstrated in-vitro activity in a broad spectrum of human cancer cell lines derived from 
both solid tumors and hematologic malignancies (IC50 ~100 nM to 500 nM).  
Further pre-clinical work in HCC cell lines has shown that BBI608 is active in vitro against both bulk tumor 
cells and cancer stem cells (CSCs) derived from HCC cell lines.  Moreover, there is evidence that BBI608 
may act synergistically with sorafenib in vitro.  Figure 1 below demonstrates in vitro activity of BBI608 
and BBI608 with sorafenib against bulk tumor cells, whereas Figure 2 shows that BBI608 and BBI608 
with sorafenib reduces the ability of CSCs to form characteristic spheres in non-adherent stem cell media 
in vitro. 




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and the cells remain viable.  Cancer stem cell markers such as CD133 and CD44 are reduced after treatment 
with BBI503.  Treatment with the combination of BBI503 + Sorafenib has also shown in vitro activity 
against CSC derived from HCC cell lines.   
 
Figure 3: BBI503 & Sorafenib Sphere Formation  
Single CSC cells were grown in suspension for 48 hrs. 
1µM BBI503 and 2 µM Sorafenib were added for 24 
hrs. Drug was removed, and cells were cultured another 
24 hours. DIC images were taken for the CSC sphere. 
Note: BBI503 compound is bright yellow, and is 
accumulated in CSC cells; blue is from Trypan Blue 
indicating dead cells. 
 
 
Additional studies were performed on bulk cancer cells derived from HCC cell lines.  Compared with the 
CSC-enriched sphere culture, bulk cells contain mainly (~ 98%) non-CSCs. In Figure 4 below, the 
combination of BBI503 and sorafenib may be synergistic in-vitro.  
Figure 4: BBI503 & Sorafenib Colony Formation 
 
Using Hep3B and Huh7 cell lines, 1000 cells per well were seeded in 6-well plates. The next day, 
the cells were treated with BBI503 0.3 µM, sorafenib 2 µM, or the combination of both for 24 
hours.  After 24 hours, the remaining cells were cultured in fresh medium for 7-10 days until 
visible colonies formed. 
1.3 
Safety and Antitumor Activity in Phase I 
1.3.1 BBI608 
A phase 1 dose escalation study (BBI608-101) in adult patients with advanced cancer was initiated to 
evaluate the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary 
anti-tumor activity of napabucasin. A modified Simon accelerated titration scheme was used for dose 
escalation, with a cycle consisting of twice-daily oral administration of napabucasin for 4 weeks, and was 
repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or other 
discontinuation criteria were met.  


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The dose of napabucasin was escalated from 20 mg to 2000 mg/day, and MTD was not reached according 
to the protocol definition.  However, further dose escalation beyond 1000 mg/day was limited by pill burden 
and gastrointestinal adverse events. In the 87 patients the most common adverse events (regardless of 
reported causality) included diarrhea (83%), fatigue (62%), abdominal pain (59%), nausea (56%), vomiting 
(52%), and anorexia (51%).  Grade 3 events included diarrhea (16%), fatigue (14%), abdominal pain (6%), 
dehydration (6%), and anemia (6%).  The recommended phase II dose (RP2D) was determined to be 500 
mg twice daily (1000 mg total daily dose).  The plasma concentration of napabucasin reached a mean 
maximal concentration of 843 ng/mL.  
BBI608 has also been combined with several chemotherapeutic agents to date.  The current safety and 
efficacy data are available in the IB (version 6.3).   
1.3.2 BBI503 
A phase 1 dose escalation study (BBI503-101) in adult patients with advanced cancer has been initiated to 
determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary 
anti-tumor activity of BBI503. A modified Simon accelerated titration scheme was used for dose escalation, 
in which BBI503 was administered orally, once daily, twice daily, or three times daily in continuous 28-
day cycles. Cycles were repeated until progression of disease, unacceptable adverse events, or anther 
discontinuation criterion was met.  
The dose of BBI503 has been escalated from 10 mg to 600 mg total daily, and a MTD has not been reached 
according to the protocol definition.  However, further dose-escalation was limited by pill burden or 
gastrointestinal adverse events (nausea, diarrhea).  BBI503 plasma concentration reached the in-vitro IC50 
and pharmacokinetic parameters maximized at 300 mg to 400 mg total daily.  The putative recommended 
phase II dose for once daily dosing is 300 mg once daily and the putative recommended phase II dose for 
twice daily dosing is 200 mg twice daily (400 mg total daily).   
BBI503 observed adverse events have been predominantly mild to moderate gastrointestinal disturbances.  
The most common events have been CTCAE grade 1 or grade 2 abdominal cramping, diarrhea, and nausea.  
Non-gastrointestinal events have included fatigue. Grade 3 events considered possibly, probably, or 
definitely related to protocol therapy have included diarrhea, fatigue, vomiting, and abdominal cramping.  
Adverse events can be managed with supportive care such as intravenous fluids and pharmacologic 
measures targeting the specific symptom.  Dose-modification or holding of dosing until symptoms improve 
and/or resolve is recommended for moderate to severe symptoms.   
Please refer to the Investigator Brochure for additional clinical data.   
In summary, BBI503 has shown an manageable safety profile, favorable pharmacokinetics, and preliminary 
signs of antitumor activity.   
1.4 
Combination Therapy for Hepatocellular Carcinoma 
Advanced HCC remains a clinical challenge.  This is due to several factors, including the chemoresistant 
nature of the disease, the toxicity profile of currently available systemic chemotherapeutic agents, and the 
general poor health and underlying liver dysfunction of HCC patients (Kelley, R 2013).  The Sorafenib 
Hepatocellular Carcinoma Assessment Protocol (SHARP) trial remains the only randomized controlled trial 
of a systemic chemotherapeutic agent to demonstrate a statistically significant survival benefit in patients 
with advanced, unresectable HCC (Bruix, J 2012; Llovet, JM 2008).  In that study, 602 patients were 
randomly assigned to receive sorafenib (400 mg twice daily) or placebo. A median Overall Survival (OS) 
of 10.7 months was observed in the treatment arm compared to 7.9 months for placebo.  Time to Tumor 
Progression (TTP) for the sorafenib and placebo arms was 5.5 months and 2.8 months, respectively.   


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The benefits achieved with sorafenib monotherapy are important, but modest in magnitude (2.8 months 
increase in median survival).  Many patients do not experience disease control, and disease control can be 
short-lived in those that do achieve it with therapy.  Unfortunately, however, no other agent has proven 
more effective.  Recent phase III trials with other regimens (FOLFOX, brivanib, sunitinib and linifanib; 
Qin, S et al, 2012; Johnson, PJ et al, 2013, Cheng, A et al 2011; Cianap, C et al, 2012) have all failed to 
demonstrate a statistically significant improvement in OS when compared to treatment with sorafenib.   
There have also been multiple studies of combination therapy using sorafenib plus an additional agent or 
regimen.  Few combinations, however, have progressed for further evaluation in the phase III, pivotal 
setting.  Those that have been evaluated in phase III trials, such as Brivanib, FOLFOX, and Erlotinib, have 
failed to demonstrate superiority to sorafenib alone.  Increased toxicity and poor quality of life were 
observed in the BRISK-FL study, and an increased incidence of hand-foot syndrome has been observed in 
combination studies with 5-FU or 5-FU derivative therapies [Dig Dis Sci. 2012 May; 57(5): 1122–1129].  
An unmet medical need exists for active systemic therapies in HCC.   
   


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2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objectives for the phase Ib and phase II portions of this study are: 
Phase Ib: 
• 
To determine the safety, tolerability, and recommended phase II dose (RP2D) of BBI608 in 
combination with sorafenib and the safety, tolerability, and recommended phase II dose (RP2D) of 
BBI503 in combination with sorafenib when administered to adult patients with advanced 
hepatocellular carcinoma who have not received previous systemic chemotherapy.   
Phase II: 
• 
To evaluate the tolerability, safety, and preliminary anti-tumor activity in patients with advanced 
hepatocellular carcinoma randomized to receive treatment with sorafenib in combination with 
BBI608, sorafenib in combination with BBI503*, or sorafenib alone; BBI608 and BBI503 will be 
administered at their respective RP2D dose levels for combination administration with sorafenib, 
which were determined during the phase Ib portion of the study. 
* Once the amendment 3 is in effect, Arm 2 in the Phase II portion will be closed for enrollment.  
2.2 
Secondary Objectives 
The secondary objectives for this study are: 
• 
To determine the pharmacokinetic profile of BBI608 administered in combination with sorafenib 
and of BBI503 administered in combination with sorafenib. 
• 
To perform biomarker studies for BBI608 administered in combination with sorafenib and for 
BBI503 administered in combination with sorafenib. 


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3 
SELECTION OF STUDY POPULATION  
This study will be conducted in patients with advanced, metastatic, unresectable and incurable 
hepatocellular carcinoma who have not received previous systemic chemotherapy and who are candidates 
for sorafenib. The study population and inclusion criteria for phase Ib and phase II are the same.   
The study will initially be conducted at selected sites in North America, and may be expanded to sites 
globally. 
3.1 
Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
1. Signed written informed consent must be obtained and documented according to  
International Conference on Harmonisation (ICH) and local regulatory requirements 
2. Histologically or cytologically confirmed hepatocellular carcinoma that is metastatic, unresectable, 
or recurrent. 
a. Patients must not be candidates for curative resection 
b. Patients who have recurrent disease after having had one or more prior resections may be 
eligible, provided that they are not candidates for further curative resection.  
c. Patients who have recurrent hepatocellular carcinoma following hepatic transplantation are 
excluded unless the following criteria are met: 
i. Transplantation was performed at least 6 months prior to the relapse of HCC. 
ii.  Patients are on stable immune suppressive therapy with no clinical evidence of 
rejection.  
iii. Are receiving ≤ 2.5 mg everolimus daily. 
d. Patients with known HIV infection are excluded.  
e. Patients with Hepatitis B are eligible provided there is no active viral replication*.  Patients 
with Hepatitis C who are not on interferon are eligible. 
3. Patients who have a diagnosis of HCC made through radiologic imaging may be eligible, provided 
they meet the following criteria according to the American Association for the Study of Liver 
Disease, AASLD (Bruix and Sherman, 2005; Bruix and Sherman, 2011): 
a. Two dynamic imaging techniques (such as 4-phase multi-detector CT or dynamic contrast-
enhanced MRI) must be used for lesions < 2 cm in diameter 
b. Typical vascularity pattern (arterial hypervascularity AND venous or delayed phase 
washout) must be present on dynamic imaging  
c. If these criteria are not met, biopsy must be performed to confirm diagnosis 
4. Patients must be candidates for sorafenib 
5. Must have had no previous systemic anti-cancer treatment, though previous loco-regional therapy 
is allowed: 
a. Prior treatment with any of the following is allowed: trans-arterial embolization, trans-
arterial chemo-embolization, percutaneous ethanol injection, radio-embolization, radio-
frequency ablation, or other ablation techniques.   
6. Must be Child-Pugh class A or class B7 albumin (no more than a score of two in albumin) 
a.  Patients with uncontrolled massive ascites or presence of hepatic encephalopathy are 
excluded 


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b.    Patients who are on therapeutic anticoagulation, their PT/INR will be assigned a score of 
one.  c 
7. Must have total serum bilirubin ≤ 3 mg/dl  
8. ≥ 18 years of age  
9. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Section 16) 
11. 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 or BBI503 dose  
12. Females of childbearing potential must have a negative serum pregnancy test 
13. Aspartate Aminotransferase (AST) and Alanine transaminase (ALT) < 5.0x the upper limit of 
normal (ULN)  
14. GFR > 35 mL/min/1.73m2 according to the Cockroft-Gault estimation.    
15. Hemoglobin ≥ 8.5 mg/dl 
16. Absolute neutrophil count  1.5 x 109/L  
17. Platelets ≥ 60 x 109/L  
18. Life expectancy ≥ 3 months   
 
*2015 ASCO guidelines for monitoring and use of antiviral therapy and prophylaxis for Hepatitis B should 
be followed 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Previous treatment with sorafenib 
2. Patients with known hypersensitivity to sorafenib or any other component of sorafenib.  
3. Previous systemic anti-VEGF or any prior systemic anti-cancer therapy, including prior treatment 
with systemic agents such as regorafenib, ramucirumab, pazopanib, or experimental agents such as 
brivanib. 
4. Have had a surgical procedure requiring general anesthesia or inpatient hospitalization for recovery 
less than 4 weeks prior to beginning protocol therapy.   
5. Have had a loco-regional procedure for the treatment of hepatocellular carcinoma (such as a 
percutaneous, trans-arterial, or radio-ablative procedure) less than 4 weeks prior to beginning 
protocol therapy.  Protocol therapy may begin a minimum of 4 weeks after such a procedure 
provided the following criteria are met: 
a. There is progression of disease documented by RECIST 1.1 
b. All adverse events from the procedure have resolved or have been deemed irreversible and 
the patient meets inclusion criteria.   
6. Any known symptomatic or untreated brain metastases requiring increase of steroid dose within 2 
weeks prior to starting on study.  Patients with treated brain metastases must be stable for 4 weeks 
after completion of that treatment.  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. 


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7. Pregnant or breastfeeding  
8. Significant gastrointestinal disorder(s) (e.g., Crohn’s disease, ulcerative colitis, extensive gastric 
and small intestine resection) such that, in the opinion of the treating investigator, absorption of 
oral medications may be impaired.     
9. Unable or unwilling to swallow BBI608, BBI503, or sorafenib capsules or tablets               
10. Uncontrolled inter-current 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), or uncontrolled infection or psychiatric illness/social situations that would 
limit compliance with study requirements (e.g. no reliable transportation). 
11. Subjects with a history of another primary cancer, with the exception of: a) curatively resected non-
melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid 
tumor with no known active disease present that, in the opinion of the investigator, will not affect 
patient outcome in the setting of current hepatocellular carcinoma diagnosis. 
12. Abnormal ECGs which are clinically significant such as QT prolongation (QTc > 480 msec), 
clinically significant cardiac enlargement or hypertrophy, new bundle branch block, or signs of 
active ischemia.  Patients with evidence of prior infarction who are NYHA functional classes II, 
III, or IV are excluded, as are patients with marked arrhythmias such as Wolff Parkinson White 
pattern or complete AV dissociation*.    
*Patients with complete or incomplete AV dissociation who have a pacemaker may be eligible for enrollment 
provided they are NYHA functional class I: “No limitation of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, or dyspnea (shortness of breath).” 
3.3 
Number of Patients 
The number of patients enrolled on this study depends on the number of cohorts enrolled in phase Ib and 
the adverse events observed.  It is expected that approximately 6 to 12 patients will be enrolled in each arm 
during phase Ib dose-escalation, for 12 to 24 patients total in phase Ib. After RP2D is determined for BBI608 
in combination with sorafenib and for BBI503* in combination with sorafenib, enrollment to a randomized 
phase II portion of the study will begin.  A total of approximately 90 patients will be randomized to one of 
three study arms: sorafenib in combination with BBI608, sorafenib in combination with BBI503, or 
sorafenib alone, so that approximately 30 patients per arm will be enrolled. Patient accrual will occur over 
a period of time dependent upon the enrollment rate.  *Once the amendment 3 is in effect, Arm 2 in the 
Phase II portion will be closed for enrollment due to BBI503 portfolio priorities and to increase efforts in 
enrolling patients on to Arms 1 and 3.  When amendment 3 was in effect, there were approximately 10 
subjects enrolled in each of the three arms, and approximately 30 patients will be enrolled in each of the 
two open arms (70 total for phase II). 
The sample size for the phase II portion provides for an evaluation of tolerability, safety, and preliminary 
anti-tumor activity (see Section 10 and Section 10.5 for details).  Briefly, enrollment will support an 
evaluation of the proportion of patients treated with combination therapy or with sorafenib alone who 
experience a grade 3 adverse event.  Enrollment also supports an evaluation of the proportion of patients 
treated with combination therapy or with sorafenib alone who are alive and without progression at 4 months 
(16 weeks) after randomization. 
Non-evaluable patients for reasons unrelated to the treatment will be replaced, such as subjects with 
exclusion criteria inadvertently randomized or subjects who withdraw for personal reasons. 


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4 INVESTIGATIONAL PLAN 
4.1 Overall Study Design 
This is an open-label Phase Ib/II study of oral study drug (BBI608 or BBI503) administered in combination 
with sorafenib to adult patients with advanced hepatocellular carcinoma (HCC).  The study will proceed 
initially as a phase Ib dose-escalation study, in which patients will be randomized to receive escalating 
doses of either BBI608 in combination with sorafenib [phase Ib Arm 1], or escalating doses of BBI503 in 
combination with sorafenib [phase Ib Arm 2].  The phase Ib portion of the study is designed to determine 
the safety, tolerability, pharmacokinetics, and recommended phase II dose (RP2D) for BBI608 plus 
sorafenib and of BBI503 plus sorafenib.   
When putative RP2D is determined for each study drug in combination with standard sorafenib dosing 
according to the criteria for determination of dose-escalation and dose limiting toxicity per-protocol, the 
phase II portion of the study will begin.   
The phase II portion is a randomized, 3-arm, open-label controlled study designed to compare the safety, 
tolerability, and preliminary anti-tumor activity in patients with advanced hepatocellular carcinoma 
randomized to receive treatment with either sorafenib plus BBI608 [phase II Arm 1], sorafenib plus BBI503 
[phase II Arm 2], or sorafenib alone [phase II Arm 3].  In the phase II portion, BBI608 and BBI503 will be 
administered at their respective RP2D dose levels for administration with standard sorafenib dosing which 
were determined during the phase Ib portion of the study.  Sorafenib will be administered at standard dose 
for both the phase Ib and phase II portions of this study.   
Note: 
Once the amendment 3 is in effect, Arm 2 in the Phase II portion will be closed for enrollment due to 
BBI503 portfolio priorities and to increase efforts in enrolling patients on to Arm 1 and 3.  
When amendment 3 being in effect, there were approximately 10 subjects enrolled in Arm 2.  
Approximately 30 patients will be enrolled in each of the two open remaining arms (70 total for phase II).   
During both the Phase Ib and Phase II portions of this study, objective (i.e. radiologic) disease assessments 
are required.  A baseline objective disease assessment is required within 14 days of starting protocol 
therapy. Per-protocol objective disease assessments will be performed every eight weeks (56 days), as 
calculated according to the date of the first dose of protocol therapy on study.  A window of ±7 days is 
allowed when scheduling radiologic disease assessments (applies to each scan individually).  Clinically 
indicated radiologic evaluations outside of this schedule are allowed (see Section 5.7, Tumor Evaluation 
Visits)  
4.2 Design - Phase Ib 
Patients will be randomized into available enrollment slots in either Arm 1, BBI608 in combination with 
sorafenib, or in Arm 2, BBI503 in combination with sorafenib.  Protocol therapy for each arm will consist 
of daily oral administration of either BBI608 or BBI503 in combination with a fixed dose of sorafenib.  
Prior to initiation of combination therapy for an individual patient, sorafenib will be administered as 
monotherapy for 14 days.  Dose-adjustment of sorafenib is allowed according to the approved product label.  
The combination regimen of study drug (either BBI608 or BBI503) plus sorafenib will be administered in 
continuous 28-day cycles until disease progression, unacceptable toxicity, or another discontinuation 
criterion is met. 
Sorafenib will be administered at a fixed dose of 400 mg twice daily (800 mg total daily dose).  This dose 
of sorafenib will be the same for each arm and for each dose-level cohort.  Sorafenib should be taken on an 
empty stomach, one hour prior to or two hours after meals.  Sorafenib should not be taken with study drug, 
and at least 2 hours should separate a dose of sorafenib from a dose of study drug. 


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Dose-escalation, determination of dose-limiting toxicity, and determination of RP2D will occur 
independently in each study arm.   
Arm 1: 
BBI608 will be administered orally, twice daily. The first dose of BBI608 should be administered 
shortly after waking in the morning. The second dose of BBI608 should be taken before bed, and 
approximately 12 hours should separate the two BBI608 doses.  BBI608 should not be taken with 
sorafenib.   
BBI608 should be administered before the first dose of sorafenib. A dose of BBI608 should be separated 
from a dose of sorafenib by at least 2 hours. It is recommended to take both BBI608 and sorafenib 
around the same time every day.  
Examples of dosing schedules consistent with these instructions can be found in the accompanying 
study manual.  The dose of BBI608 to be administered will depend on the assigned dose-level cohort 
as follows in the table below: 
BBI608 Dose Level 
BBI608 Dose & Schedule 
BBI608 Dose-Level I 
160 mg Twice Daily 
BBI608 Dose-Level II 
240 mg Twice Daily 
Initially, 3 patients will be enrolled at BBI608 Dose-Level 1.  Dose-escalation will proceed with cohorts 
of three to six patients according to the Criteria for Dose Escalation and Criteria for Determination of 
Dose-Limiting Toxicity (DLT).  
Intermediate or additional dose-levels are permitted upon agreement with the Principal Investigator and 
medical monitor for the Sponsor. The RP2D determined for BBI608 in combination with standard 
sorafenib dosing during the phase Ib portion of the study will be the starting dose for the BBI608 plus 
standard sorafenib arm of the randomized phase II portion of the study.   
Arm 2: 
BBI503 will be administered orally, daily. The daily dose of BBI503 will be administered before bed. 
BBI503 should not be taken with sorafenib.  
BBI503 is taken 1 hour prior to meals or 2 hours after.  A dose of BBI503 and a dose of sorafenib 
should be separated by at least 2 hours.  
The dose of BBI503 to be administered will depend on the assigned dose-level cohort as follows in the 
table below: 
BBI503 Dose Level 
BBI503 Dose & Schedule 
BBI503 Dose-Level I 
100 mg Once Daily 
BBI503 Dose-Level II 
200 mg Once Daily 
Initially, 3 patients will be enrolled at BBI503 Dose-Level 1.  Dose-escalation will proceed with cohorts 
of three to six patients according to the Criteria for Dose Escalation and Criteria for Determination of 
Dose-Limiting Toxicity (DLT).   


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Intermediate or additional dose-levels are permitted upon agreement with the Principal Investigator and 
medical monitor for the Sponsor.  The total daily dose of BBI503 may be divided into sub-doses.  The 
RP2D determined for BBI503 in combination with standard sorafenib dosing during the phase Ib 
portion of the study will be the starting dose for the BBI503 plus standard sorafenib arm of the 
randomized phase II portion of the study.   
RP2D Determination 
In both Arm 1 and Arm 2, dose escalation will proceed with the purpose of determining a recommended 
Phase 2 dose (RP2D).  Dose escalation will proceed in each arm independent of the other arm.  The goal of 
dose escalation in Arm 1 is to determine RP2D of BBI608 in combination with sorafenib.  The goal of 
dose-escalation in Arm 2 is to determine RP2D of BBI503 in combination with sorafenib.  In both arms, if 
a patient discontinues study participation for reasons other than DLT, that patient may be replaced so that 
the safety of the dose-cohort can be fully evaluated.  
For both arms, the decision to escalate the dose of study drug in combination with sorafenib is based on the 
adverse events observed and the criteria for determination of dose-escalation (dose-escalation decision 
rules) in Table 1 below.  The criteria for determination of dose-escalation will be applied independently to 
each arm.   
Table 1: Criteria for Determination of Dose Escalation 
 
Number of Subjects with 
DLT at a Given Dose Level 
 
Escalation Decision Rule 
 
0 out of 3 
 
Enter 3 subjects at the next dose level 
 
> 2 
 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional subjects will be entered 
at the next lower dose level if only 3 subjects were treated 
previously at that dose. 
 
1 out of 3 
 
Enter at least 3 more subjects at this dose level. 
• 
If 0 of these 3 subjects experience DLT, proceed to the 
next dose level 
• 
If 1 or more of this group experience DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
subjects will be entered at the next lower dose level if 
only 3 subjects were treated previously at that dose. 
 
<1 out of 6 at highest dose level 
below 
the 
maximally 
administered dose 
 
This is the maximally tolerated dose.  RP2D will not exceed 
MTD.   
For each arm, the DLT and Escalation Decision Rules outlined in Table 1 apply to a given administration 
schedule independently.  The recommended phase II dose will be determined based on the clinical safety 
and tolerability observed, as well as on pharmacokinetics and pharmacodynamics of the dosing cohort.   
The determination of RP2D in each study arm will not be based solely on DLT observed during the DLT 
observation period.  The determination of RP2D will include an assessment of Grade 2 adverse events of 
long duration as well as toxicities beyond the first cycle.   


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Once a putative recommended phase 2 dose (RP2D) has been determined, up to 6 additional patients 
evaluable for determination of dose-escalation may be enrolled to confirm safety and tolerability.  A 
putative RP2D determination may be updated.   
The phase Ib portion of the study will be declared to be completed once RP2D for BBI608 in combination 
with sorafenib and RP2D for BBI503 in combination with sorafenib are both determined.    
The principal investigator and study staff at all study sites will be notified when the phase Ib portion of the 
study has ended.  Receipt of this notification must be confirmed.  Once the phase Ib portion has ended, 
further enrollment will be in the randomized phase II portion.  As such, during the informed consent process 
for the phase II portion of the study, potential study patients must be made aware of the possibility of being 
randomized to receive standard of care (sorafenib) alone.    
4.3 Design – Phase II 
The phase II portion of the study will begin when RP2D is determined for each agent in combination with 
sorafenib.  Patients enrolled into the phase Ib portion will not be eligible for enrollment into the phase II 
portion.   
The primary aim of the phase II portion is to evaluate the tolerability, safety, and preliminary anti-tumor 
activity in patients randomized to each arm above.  Sorafenib is the current standard of care for patients 
with advanced HCC.  The evaluation of safety and activity planned for the phase II portion of this study 
will inform the design of further trials. (see Section 10.5 in Section 10 for further details).   
The phase II portion of the study will require patients to meet the same inclusion and exclusion requirements 
as the phase Ib portion, which are outlined in Section 0 and in Section 3.2.  After completing all screening 
tests and ensuring all criteria are met, study sites will submit a randomization request for those patients who 
are eligible for enrollment.  Patients will be centrally randomized in an open label fashion in a 1:1:1 ratio 
to one of the following three arms outlined in Table 2 below: 
Note: 
Once the amendment 3 is in effect, Arm 2 in the Phase II portion will be closed for enrollment due to 
BBI503 portfolio priorities and to increase efforts in enrolling patients on to Arm 1 and 3.  
At the time of the amendment 3 there were approximately 10 subjects enrolled in Arm 2, therefore a total 
of approximately 70 patients will be enrolled in the phase II portion of the study, or approximately 30 
patients will be enrolled in each of the two open remaining arms.  
Table 2: Phase II Study Arms 
Study Arm 
Backbone Chemotherapy 
Investigational Agent 
Agent 
Starting Dose 
Agent 
Starting Dose 
Phase II Arm 1 
Sorafenib 
400 mg Twice Daily 
BBI608 
Phase Ib RP2D 
Phase II Arm 2 
Sorafenib  
400 mg Twice Daily 
BBI503 
Phase Ib RP2D 
Phase II Arm 3  
Sorafenib  
400 mg Twice Daily 
- 
- 
Once randomized, patients are to begin protocol therapy within 72 hours of randomization.  There are only 
slight differences in the patient visit schedule and schedule of assessment for patients enrolled onto the 
phase II portion of the study.  The study visit schedules are outlined in section 5.   
The schedule of administration for protocol therapy is the same in both the phase Ib and phase II portions 
of the study.  In addition, for both phase Ib and phase II, the backbone chemotherapy is the standard dosing 
of sorafenib. 


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For patients enrolled to the phase II portion of the study, per-protocol objective (radiologic) disease 
assessments (see Section 5.7.2) should occur every 8 weeks (56 days) until disease progression is 
documented according to RECIST 1.1 and mRECIST for HCC.  Protocol therapy may be continued in an 
open-label fashion until the investigator determines that the patient is no longer deriving clinical benefit. 
If sorafenib is discontinued for any reason, study drug (BBI608 or BBI503) may be continued.  If a patient 
is randomized to Phase II Arm 1 or Phase II Arm 2, and study drug is permanently discontinued, patients 
will begin the follow-up portion of the protocol assessment schedule (see Section 5.10), and may receive 
any further treatment as determined by the treating investigator, including sorafenib.  Objective (radiologic) 
disease assessments should continue to be obtained every 8 weeks in these patients until progression is 
documented according to RECIST 1.1 and mRECIST for HCC.       
If RP2D for either BBI608 or BBI503 in combination with sorafenib is updated during the course of the 
phase II portion of the study, then patients randomized to that study arm will be administered study drug at 
the updated RP2D.  If needed, up to 30 patients total may be enrolled in a study arm at a given dose of study 
drug during the phase II portion of the study.   
 
 
 
4.4 Rationale for Study Design  
HCC is a global disease with a marked unmet medical need for effective systemic therapy.  The scientific 
literature suggests that cancer stem cells may play a role in resistance to effective chemotherapies. Thus, 
there is a strong rationale to clinically evaluate the addition of an agent which targets cancer stem cells to 
a therapy such as sorafenib which has proven effectiveness in HCC.  
In addition to clinical safety and tolerability, pharmacokinetic and pharmacodynamic data will be collected 
on this trial in order to establish the optimal dosing regimen for both BBI608 and BBI503 in combination 
with sorafenib. The phase II portion will establish a body of evidence on which to base further clinical 
development.     
 
4.5 Selection of Dose  
The starting doses of study drug (either BBI608 or BBI503) for phase Ib are based on clinical experience 
during the monotherapy phase I evaluation of both agents.  Doses were selected which were well tolerated 
as monotherapy, and which were well below the maximally administered dose for each agent.   
For the phase Ib portion, the starting dose of BBI608 in combination with sorafenib is 160 of BBI608 taken 
twice daily.  This is 33% of the BBI608 monotherapy RP2D (480 mg twice daily, 960 mg total daily dose), 
and 16.7% of the maximally administered dose during the monotherapy phase I trial (1000 mg twice daily, 
2000 mg total daily dose).  Of note, MTD was not determined in the BBI608 monotherapy phase I dose-
escalation trial.  
The starting dose of BBI503 in combination with sorafenib is 100 mg once daily.  This is 33% of the 
BBI503 monotherapy once daily RP2D (300 mg once daily), and 16.7% of the maximally administered 
dose during the monotherapy phase I trial (200 mg three times daily and 300 mg twice daily, or 600 mg 
total daily dose).  Of note, MTD was not determined in the BBI503 monotherapy phase I dose-escalation 
trial.   
The dose of BBI608 and of BBI503* for the phase II portion of the study will be determined during the 
phase Ib portion of the study.  The starting dose for phase II Arm 1 (sorafenib plus BBI608) will be the 
RP2D of BBI608 in combination with sorafenib as determined during dose-escalation of phase Ib Arm 1.  
The starting dose for phase II Arm 2 (sorafenib plus BBI503) will be the RP2D of BBI503 in combination 
with sorafenib as determined during dose-escalation of phase Ib Arm 2.   


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* Once the amendment 3 is in effect, Arm 2 in the Phase II portion will be closed for enrollment. 
 
4.6 Criteria for Dose Escalation and Determination of Dose-Limiting Toxicity 
Patients are considered evaluable for determination of DLT and for determination of dose-escalation if they 
have been exposed to at least 28 days of continuous daily administration of study drug (BBI608 or BBI503) 
in combination with sorafenib at a compliance level of at least 80% for the combination regimen.   
Compliance for study drug (either BBI608 or BBI503) and sorafenib is calculated by dividing the number 
of pills ingested by the total number of pills assigned to be ingested (see Section 7.4).  The assigned dose 
of BBI608 or BBI503 is that determined by the dose-level cohort into which the patient is enrolled.  The 
assigned dose of sorafenib is the dose administered at the start of combination therapy, as determined during 
the 2-week run-in period.  The starting dose of sorafenib is 400 mg twice daily, and dose-reductions 
according to standard of care are allowed.  Events meeting DLT definition that occur during the sorafenib 
run-in period will not be considered DLTs.  Events occurring at any time that are determined to be due 
solely to sorafenib will not be considered DLTs.   
Enrollment at the next dose level of study drug (either BBI608 or BBI03) and/or enrollment of additional 
patients into the ongoing cohort will be based on the tolerability and safety observed in evaluable patients, 
according to criteria described below:  
• 
If zero treated patients experience a DLT (defined below) by Day 28 of continuous daily dosing, 
then dose escalation will occur. 
• 
If one treated patient experiences a DLT (defined below) by Day 28 of continuous daily dosing, 
then an additional three patients will be enrolled for a total of six patients treated at the same dose 
level.  Escalation will occur if no additional DLTs are seen in that cohort (one of six patients). 
• 
If two or more treated patients at a dose level experience a DLT (defined below) by Day 28 of 
continuous daily dosing, this will be the maximally administered dose.     
Once the maximally administered dose is determined, a total of six patients will be treated at the previous 
dose level.    
The BBI medical Monitor and Principal Investigator will review all significant combination therapy related 
toxicities to determine if the dose escalation schedule requires modification.  Intermediate or additional 
dose levels or an alternate administration schedule may be assigned to a cohort after agreement between 
the BBI Medical Monitor and the Principal Investigator.  
 
4.7 Dose-Limiting Toxicity 
Dose-Limiting Toxicity (DLT) is defined as the occurrence of any of the following toxicities possibly, 
probably, or definitely related to study drug (either BBI608 or BBI503) or to study drug in combination 
with sorafenib during the first 28 days of combination therapy, unless there is a clear alternative 
explanation:   
• 
CTCAE (Common Terminology Criteria for Adverse Events) Grade 4 hematological toxicity. 
• 
Grade 3 thrombocytopenia in the presence of active bleeding. 
• 
Grade 3 or 4 non-hematological toxicity, except for Grade 3 nausea/vomiting/anorexia, diarrhea, 
or fatigue, symptoms that will be considered DLTs only if they persist more than seven (7) days 
despite optimal medical management.  Grade 4 toxicity will be considered DLT.   
Alopecia will not be considered a DLT.  Assessment of DLTs will occur during the first 28 days of BBI608 
or BBI503 therapy in combination with sorafenib.  DLTs will be determined from both adverse events and 
changes from baseline in physical examination findings and laboratory parameters.   


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The criteria for determination of DLTs will apply to a given administration schedule independently.  
Patients who discontinue protocol therapy for a reason other than a DLT may be replaced in order to fully 
evaluate a given dose-level.   
 
4.8 Study Duration  
For both the phase Ib and phase II components of the study, patients will receive treatment with combination 
therapy (either BBI608 or BBI503* in combination with sorafenib) until the investigator has determined 
that the patient is no longer likely to receive clinical benefit due to progression of disease, unacceptable 
toxicity, or another discontinuation criterion (see Section 5.9).  It is expected that most patients will receive 
between one and four cycles of combination therapy for a treatment period of 4 to 16 weeks.  It is expected 
that patient accrual for both the phase Ib and phase II portions of the trial will occur over a period of 12-18 
months, with an additional 12 months to complete follow-up.   
* Once the amendment 3 is in effect, Arm 2 in the Phase II portion will be closed for enrollment. 


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5 STUDY VISITS 
5.1 
Overview 
For the phase Ib portion of the study, study visits will consist of a Pre-Study Evaluation, during which the 
patient will be evaluated to determine eligibility for entry into the study; a Cycle 1, Day 1 Visit at the start 
of the sorafenib monotherapy run-in period; a phone call to patients on Cycle 1, Day 8, which is the 
approximate mid-point of the 14-day sorafenib monotherapy run-in period; a Cycle 1, Day 15 Visit, which 
is the start of combination therapy; a Cycle 1, Day 22 visit; and then regular evaluations every 2-weeks 
starting on Cycle 2, Day 1.  
For the phase II portion of the study, study visits will also involve a Pre-Study Evaluation.  Cycle 1 visits 
will include a brief visit on Cycle 1, Day 1 (the start of the sorafenib monotherapy run-in period); a phone 
call to patients on Cycle 1, Day 8; a full visit on Cycle 1, Day 15 (the start of combination therapy); and a 
visit on Cycle 1, Day 22.  In Cycle 2, there will be visits on Cycle 2, Day 1 and on Cycle 2, Day 15.   Starting 
in Cycle 3, the only required in-person visit is on the first day of the study cycle (i.e., Cycle 3, Day 1; Cycle 
4, Day 1, etc.).   
During the phase II portion, an in-person visit on Cycle 3, Day 15 is optional, and is optional on Day 15 of 
each subsequent cycle, provided patients are stable.  If the in person visit is not performed on Cycle 3, Day 
15 or on Day 15 of a subsequent cycle, study staff are to reach out to the patient with a phone call.   
For both phase Ib and phase II, an End-of-Study Evaluation will also be completed between 14 and 30 days 
after the last dose of protocol therapy; See Section 14 for a schedule of Assessments).   
In general, unless otherwise noted, a window of ± 2 days is allowed when scheduling protocol visits and 
evaluations.  If, due to unforeseen circumstances, frame-shifting of a study cycle or patient visit schedule 
occurs beyond the allowable window of ± 2 days, the medical monitor for the Sponsor should be notified 
of the alternate schedule.  The protocol window of ± 2 days may then be applied to the frame-shifted 
schedule.   
Unscheduled clinical assessments during a study cycle are allowed, but should not replace a per-protocol 
study visit unless it is within the ± 2 day window.  During the phase II portion of the study, an unscheduled 
visit during Cycle 3 or beyond will satisfy the requirement for Day 15 patient contact provided it was +/- 7 
days from Day 15 of a given cycle, using the date of the start of the cycle as reference.   
5.2 
Informed Consent 
Patients who agree to participate will sign the approved informed consent and will be provided a copy of 
the signed document.   
Informed consent should be obtained within approximately one month prior to Run-In Day 1.  An 
appropriate informed consent must be completed prior to undergoing any laboratory or radiologic 
evaluations that are specifically being performed for the purpose of screening for this study.  However, 
assessments or laboratory evaluations that have been performed as a part of standard of care (and not 
specifically for this study) may be used to qualify for enrollment.  All screening procedures should be 
performed within the time frames indicated in the sections below.   
The treating investigator must verify that the patient meets all inclusion/exclusion criteria.  The patient is 
considered enrolled into the study when he or she begins Cycle 1, Day 1.   
A log will be kept of all patients who sign informed consent.  This “screening log” will indicate whether 
the consented patient was enrolled; if the patient was not enrolled, then the log will indicate the reason for 
non-enrollment.  Recording of official study data on Case Report Forms (CRFs) is only required for those 
patients who enroll in the study (who begin Run-In Day 1).   


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In addition, any adverse events (AEs) that occurred as a result of screening tests that would not have 
otherwise been performed should be recorded. 
5.3 Pre-Study Evaluations (Baseline)  
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 Pre-Study evaluation may be held up to 5 days (+2) prior to the first dose of sorafenib and/or study 
drug (either BBI608 or BBI503).  The following evaluations will be obtained (unless otherwise obtained as 
a part of standard of care).   
• 
Medical history, including resolved medical/surgical conditions, active concurrent medical 
conditions/adverse events, concurrent medications, as well as detailed history of current cancer 
diagnosis, treatment, and response to treatment (see Section 6.1). 
• 
Vital signs (weight, temperature, blood pressure, height, respiration and pulse) and Physical 
examination, including documentation and measurement of any external or palpable subcutaneous 
lesions (see Sections 9.1.2 and 9.1.3) 
• 
ECOG performance status  (see Section 16) 
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3);  
• 
Urinalysis (see Section 6.3)  
• 
Serum pregnancy test (if applicable) 
• 
Serum AFP level* (see Section 6.3) 
• 
Electrocardiogram* 
• 
Assess Child Pugh Class 
• 
Optional tumor biopsy, if applicable* (see Section 6.5.2) 
• 
Tumor lesion measurement and staging according to RECIST 1.1 as well as modified RECIST for 
patients with HCC [computed tomography (CT) of the chest, abdomen, and pelvis with tri-phasic 
liver scan or magnetic resonance imaging (MRI) of the abdomen and pelvis with contrast plus a 
CT scan of the chest without contrast in case of allergic reaction to CT scan contrast despite 
appropriate pre-treatment] ** 
*These do not need to be repeated if they were done within 7 days of this visit           
**Imaging obtained that meets these specifications can be used as the baseline assessment if it was obtained 
within two weeks ± 7 days of Cycle 1, Day 1.  
Note: 
After the amendment 3 was in effect, Arm 2 in the Phase II portion was closed for enrollment due to BBI503 
portfolio priorities and to increase efforts in enrolling patients on to Arm 1 and 3.  
At the time of the amendment 3 being in effect, there were approximately 10 subjects enrolled in Arm 2 
and approximately 30 patients remains to be the targeted sample size  in each of the two open remaining 
arms, therefore, the total actual sample size in Phase II in the end is projected to be approximately 70 
patients after the amendment 3.  
 
5.4 
On-Study Evaluation & Assessment Schedule │ Cycle 1  
The patient will be administered sorafenib monotherapy for the first two weeks of Cycle 1, which can also 
be termed “sorafenib run-in”.  The goal of the run-in period is to establish the tolerability of sorafenib prior 
to initiating combination therapy with study drug (either BBI608 or BBI503).   


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Sorafenib will be obtained by the patient during this study as a standard-of-care medication; sorafenib will 
not be provided by study Sponsor.   
Time required for the patient to initially obtain sorafenib should be taken into consideration when 
scheduling screening evaluations.  Throughout the study, sorafenib will be supplied as a standard of care 
medication, guided by institutional and manufacturer policy.   
5.4.1 Cycle 1, Day 1 │ Start of Sorafenib Run-In 
• 
Patient begins sorafenib dosing at 400 mg twice daily (800 mg total daily dose).   
• 
Schedule radiologic assessments for 8 weeks (56 days) from the date of Cycle 1, Day 1 (a 
scheduling window of ± 7 days is allowed for each radiologic assessment) * 
• 
Vital signs (temperature, blood pressure, respiration and pulse) and weight 
• 
AE assessment 
• 
Review concomitant medications 
 
*Radiologic evaluations do not need to correlate with study cycles.  The per-protocol assessments should 
be performed every 8 weeks regardless of study cycle count.  As such, per-protocol radiologic assessments 
should be scheduled in advance once the first dose of sorafenib is administered on Cycle 1, day 1 (Run-In 
Day 1).         
5.4.2 Cycle 1, Day 8 │ Mid Run-In (Phone Call is allowed) 
• 
Phone call to patient to assess adverse events with sorafenib monotherapy 
• 
Review concomitant medications  
• 
If visit is held in person, assess vital signs 
5.4.3 Cycle 1, Day 15 │Start of Combination Therapy 
The assessments on Cycle 1, Day 15 may be performed before, after, or both before and after the 
administration of study drug (either BBI608 or BBI503) as indicated below.  Assessments performed before 
the administration of study drug are to characterize any objective effects of sorafenib monotherapy prior to 
the initiation of combination therapy.    
For the phase Ib portion of the study, both sorafenib and study drug should be administered in clinic to 
accommodate pharmacokinetic evaluations.  The administration schedule is according to study arm and is 
outlined in the study procedure manual.    
For both the phase Ib and phase II portions of the study, the following C1D15 assessments should be 
performed prior to the first dose of study drug for patients randomized to receive either BBI608 or BBI503 
in combination with sorafenib.  If patients in Phase II have been randomized to receive sorafenib alone 
[Arm 3 ], the following labs are still required but may be obtained at any time on C1D15 (either before or 
after dosing with sorafenib on that day): 
• 
Physical exam (including vital signs, weight) 
• 
ECOG performance status (see Section 16) 
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3)  
• 
Electrocardiogram prior to first dose of study drug 
• 
Serum AFP  
• 
AE assessment 
• 
Concomitant medications  


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After the above assessments are performed, study drug (either BBI608 or BBI503) may be initiated for 
those in the phase Ib portion of the study and for those in the Phase II portion who have been randomized 
to either [Arm 1] or [Arm 2*].  For those patients administered a dose of study drug (either BBI608 or 
BBI503), the following assessments should be performed after receiving the dose: 
• 
Phase Ib Only: Blood samples for pharmacokinetics (see Section 6.4). 
• 
Phase Ib Only: Electrocardiogram pre dose and approximately 3.5 hours after the first dose of study 
drug (either BBI608 or BBI503) dispense 14-day supply of study drug (either BBI608 or BBI503) 
• 
Dispense two (2) days of study drug (either BBI608 or BBI503) dosing to be kept as “extra doses” 
by patient during study in case of loss or issues with visit scheduling (see Pharmacy Manual) 
The procedures above do not apply to those in the phase II portion who have been randomized to [Arm 3 ], 
sorafenib alone. 
* Once the amendment 3 is in effect, Arm 2 in the Phase II portion will be closed for enrollment. 
5.4.4 Cycle 1, Day 16 │ Phase Ib Arm 2 Only 
• 
Phase Ib Arm 2 Only:  Blood samples for pharmacokinetics (see Section 6.4). 
• 
Assess adverse events 
5.4.5 Cycle 1, Day 22 
• 
Vital signs, Weight 
• 
Assess adverse events 
• 
Record concomitant medication 
 
 
5.5 
On-Study Evaluation & Assessment Schedule │ Cycle 2 
5.5.1 Cycle 2, Day 1  
For both Phase Ib and Phase II, patients will have the following assessments: 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
ECOG performance status 
• 
Physical examination  
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Serum AFP (see Section 6.3) 
• 
Assess adverse events 
• 
Record concomitant medication 
• 
Dispense 28 day supply study drug (either BBI608 or BBI503)* 
*2 days of “extra doses” may be re-dispensed at a monthly visit if it was needed during the preceding cycle  
5.5.2 Cycle 2, Day 15  
Patients receiving BBI608 should take their dose of protocol therapy in clinic on this day.   
• 
Vital signs, Weight 
• 
Assess adverse events 
• 
Record concomitant medication 


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• 
Blood samples for pharmacokinetics (Section 6.4)  
• 
Phase Ib Only: Electrocardiogram approximately 3.5 hours after morning dose of BBI608 or 
approximately 13 hours after previous night dosing of BBI503 
• 
Phase II: Electrocardiogram at least 3.5 hours after morning dose of BBI608 if patient has been 
taking the doses regularly, otherwise this assessment would be moved to C3D1 or subsequent visit. 
The electrocardiogram is required for patients on all arms. Optional on-treatment tumor biopsy* 
 
*If the optional on-treatment tumor biopsy is scheduled on a day other than when pharmacokinetic blood drawn are 
obtained, then a single blood draw for determination of plasma study drug levels is required at the time of the biopsy. 
The on-treatment biopsy can be performed beyond the window for the visit due the complexity of the procedure.   
 
5.6 
On-Study Evaluation & Assessment Schedule │ Cycle 3 and Subsequent Cycles 
5.6.1 Cycle 3, Day 1 (and Day 1 of all subsequent study cycles) 
The following assessments will also be performed: 
• 
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
• 
Physical examination  
• 
ECOG performance status 
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Serum AFP (see Section 6.3) 
• 
Assess adverse events 
• 
Record concomitant medication 
• 
Dispense study drug (either BBI608 or BBI503) (28 day supply) * 
*2 days of “extra doses” may be re-dispensed at a monthly visit if it was needed during the preceding cycle  
5.6.2 Cycle 3, Day 15 (and Day 15 of all subsequent cycles) * 
• 
Vital signs, Weight 
• 
Assess adverse events 
• 
Record concomitant medication 
*These study visits do not need to be in-person.  If a patient is not seen in-person, he or she should be contacted by 
phone in order to assess adverse events and record concomitant medication.  Vital signs and weight need only be 
obtained if there is an in-person visit.   
5.7 
Tumor Evaluation Visits 
5.7.1 Baseline 
Baseline radiologic evaluation of chest, abdomen, and pelvis of sufficient quality to determine presence of 
disease according to RECIST and mRECIST for HCC is required prior to starting protocol therapy.  This 
is defined as computed tomography (CT) with intravenous contrast of the chest, abdomen, and pelvis with 
tri-phasic liver scan.  For those with an allergic reaction to intravenous CT contrast despite appropriate pre-
treatment measures, magnetic resonance imaging (MRI) of the abdomen and pelvis with gadolinium plus a 
non-contrast CT scan of the chest is required.   


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Radiologic assessments satisfying the above requirements that are obtained within 14 days of the first dose 
of sorafenib (Cycle 1, Day 1) may be used as baseline imaging.   
5.7.2 Per-Protocol 
Per-protocol radiologic assessments will be performed every eight weeks (56 days), as calculated according 
to the date of the first dose of the sorafenib run-in period.  A window of ±7 days is allowed when scheduling 
radiologic disease assessments (applies to each scan individually).  Per-protocol radiologic assessments are 
defined as a computed tomography (CT) with intravenous contrast of the chest, abdomen, and pelvis with 
tri-phasic liver scan.  For those with an allergic reaction to intravenous CT contrast despite appropriate pre-
treatment measures, per-protocol evaluation with magnetic resonance imaging (MRI) of the abdomen and 
pelvis with gadolinium plus a non-contrast CT scan of the chest is required.   
Additional radiologic evaluations when clinically indicated are allowed.  However, evaluations obtained 
for clinical indications cannot be substituted for per-protocol radiologic assessments unless they also satisfy 
the above per-protocol definition of radiologic assessment.    
Per-Protocol radiologic evaluations should be performed every 8 weeks (56 days) until radiologic disease 
progression is observed according to both RECIST 1.1 and modified RECIST for patients with HCC.  If 
protocol therapy is permanently discontinued for any reason without documentation of PD per RECIST 1.1 
and mRECIST for HCC, per-protocol imaging evaluations should continue every 8-weeks until criteria for 
disease progression are satisfied according to both RECIST 1.1 and mRECIST for HCC.   
Patients with an imaging assessment which meets criteria for either complete response (CR) or partial 
response (PR) according to RECIST 1.1 or mRECIST should have a repeat, confirmatory, radiologic 
assessment approximately 4 weeks after the assessment in which CR or PR criteria were met.  After the 
confirmatory image, radiologic assessments return to the every 8 week schedule.   
If, at any time, a determination is made for a study subject to discontinue protocol therapy, the treating 
investigator should determine the likelihood that the patient will be able to attend the next scheduled 
radiologic assessment.  If the treating investigator feels it is unlikely that a patient will be able to obtain the 
next scheduled per-protocol radiologic assessment, a per-protocol radiologic assessment should be obtained 
as soon as possible (a minimum of 4 weeks, however, should elapse between per-protocol assessments).   
Tumor response will be evaluated using the guidelines for Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) and modified RECIST for patients with HCC.  Highlights of these guidelines are contained 
in Section 9. 
In general, for each radiologic imaging assessment obtained during the study, the following information 
and documentation is required: 
- 
Completed RECIST 1.1 and mRECIST for HCC worksheets (provided by Sponsor) that document 
lesion measurements and descriptions 
- 
De-identified, dictated, radiology report of the image (see Section 5.7.4) 
De-identified digital images and/or complete copies of the digital imaging study may be requested from 
study sites (see Section 5.7.4).   
5.7.3 Patient Disposition & RECIST Criteria 
RECIST criteria serve to categorize clinical radiologic images.  RECIST categorization alone should not 
determine continuation or discontinuation of protocol therapy in a patient.  Given that both study drugs 
(BBI608 and BBI503) have a unique mechanism of action that targets cancer stem cells, study drug therapy 
may be continued in a patient who is clinically well but who meets criteria for “Progressed Disease” per 
RECIST (either RECIST 1.1 or modified RECIST for patients with HCC).  Continuation of study drug 
(either BBI608 or BBI503) therapy in this context is allowed provided that no further standard, approved 


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treatment options exist, and provided that the investigator concludes that the potential benefit to the patient 
outweighs the potential risk.   
5.7.4 Documentation and Digital Files 
Clinical site staff will be responsible for collection and documentation of those lesion measurements 
required to complete response assessments according to RECIST 1.1 guidelines and modified RECIST 
guidelines for patients with HCC.  Worksheets will be provided on which measurements for target and non-
target lesions using both RECIST 1.1 and mRECIST for HCC can be documented.  Please refer to Section 
9 for further information on definitions and RECIST guidelines.   
Quantitative image measurements and qualitative image characteristics according to RECIST guidelines 
will be documented in study Case Report Forms (CRFs).  For exploratory purposes, the Sponsor may collect 
additional information from patient radiologic images.  Examples of additional information include but are 
not limited to: de-identified radiology reports or dictations, digital copies of de-identified radiologic images, 
and/or complete de-identified image files.    
5.8 
End of Study Evaluation 
For both phase Ib and phase II, all patients should be seen 14 to 30 days after discontinuation of protocol 
therapy.  This is the End of Study (EOS) visit.  The following assessments will be made during the end of 
study visit: 
• 
Physical examination 
• 
ECOG performance status  
• 
Vital signs  (weight, temperature, blood pressure, respiration and pulse) 
• 
Hematology (see Section 6.3) 
• 
Blood chemistry (see Section 6.3) 
• 
Urinalysis (see Section 6.3) 
• 
Serum AFP (see Section 6.3) 
• 
Assess Child Pugh Class 
• 
Tumor measurements and staging if radiologic progression has not yet been documented on study.  
That is, if a patient discontinues protocol therapy due to radiologic progression of disease, an End 
of Study imaging assessment is not required.   
• 
Assess adverse events 
• 
Record concomitant medications 
Patients who are identified at the EOS visit as having persistent adverse events related to study drug (either 
BBI608 or BBI503) should continue to be followed on a monthly basis (or more frequently if clinically 
indicated) until resolution of study drug - related adverse events or until the AEs are deemed irreversible.    
Any Serious Adverse Events (SAEs) that occur up to 30 days after the last dose of study drug (either BBI608 
or BBI503) will be reported to the Sponsor regardless of assessed causality (also see Section 8.2).   
5.9 
Discontinuation from Study 
Patients may be removed from the study at any time if they meet any of the following criteria: 
• 
Progression of disease* 
• 
Noncompliance with any part of the study, as evaluated by the Principal Investigator and Medical 
Monitor 
• 
Patient request 
• 
Withdrawal of consent 
• 
Lost to Follow-up despite documented efforts at contact 


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• 
Clinically unacceptable adverse events despite optimal treatment or dose reduction. 
• 
Death  
*Since study drug (either BBI608 or BBI503) targets cancer stem cells, patients may continue study drug 
(either BBI608 or BBI503) administration with or without sorafenib beyond progression per RECIST if the 
investigator concludes that the potential clinical benefits outweigh potential risks. 
5.9.1 Dates Associated with Discontinuation from Study 
The following clarifies important dates at the end of study treatment: 
Date of Last Dose: The date that the last dose of study medication is taken (either BBI608 or 
BBI503).  The Date of Last Dose does not necessarily need to be the Date 
Off Active Study.   
Date Off Active Study: The date when both the patient and the investigator/study team understand 
the patient to be off of active protocol treatment.  In most cases, this will be 
the same as the Date of Last Dose; however, it does not need to be the case.  
In addition, the Date Off Active Study may not coincide with a formal study 
visit.   
End of Study Visit: A formal study visit held 14 to 30 days after the Date of Last Dose.   
5.10 Follow Up After Treatment Discontinuation 
For both the phase Ib and phase II portions of the study, the follow-up phase of the study will begin after 
the EOS study visit has been completed.  Patients will be followed for specified clinical endpoints (both 
primary safety and secondary exploratory efficacy endpoint), and other important information such as post-
protocol therapy.   
As specified in Section 5.7.2, per-protocol imaging (every 8 weeks/56 days) should continue until criteria 
for disease progression according to both RECIST 1.1 and mRECIST for HCC are met.   
There are no further visits required specifically for the study after the EOS visit, with the exception of 
radiologic assessments every 8 weeks until progression of disease is documented according to both RECIST 
1.1 criteria and mRECIST for patients with HCC criteria.    
The clinical parameters and endpoints for follow-up after a patient permanently discontinues study drug 
(either BBI608 or BBI503) administration are specified in table below, as is the recommended follow up 
frequency.  Follow-up and information collection is intended to be accomplished through review of the 
local medical record system by site study staff and/or study CRAs-Monitors.  Contact with the primary 
oncologist and/or primary care physician for a given patient may also be required.   
 


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Table 3: Clinical Parameters for Post-Protocol Therapy Follow-Up 
Endpoint 
Description 
Follow-Up Frequency 
Performance Status 
Decline 
First date when ECOG performance 
status of  ≥ 3 is documented, if possible 
Evidence for clinical endpoints 
will be assessed monthly for the 
first 6 months after discontinuing 
study drug (either BBI608 or 
BBI503)  
Then, 
Quarterly from 6 months to 18 
months after discontinuing study 
drug (either BBI608 or BBI503) 
Then, 
Semi-annually thereafter 
Subsequent Therapy 
Names and dates of anti-cancer 
treatment administered after permanent 
study drug (either BBI608 or BBI503) 
discontinuation.  “Clinical Trial” can 
also be used if agent name is not 
publically available 
Objective Disease 
Progression 
following 
subsequent therapy 
Date criteria for RECIST 1.1 and/or 
mRECIST for HCC categorization of 
“PD” are met after starting any post-
protocol therapy, if possible* 
Survival 
Date of death due to any cause 
*Passive follow-up only of radiologic imaging obtained following initiation of any post-protocol therapy 
 


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6 STUDY PROCEDURES 
6.1 
Medical History 
A complete medical history will be obtained.  The components will include, but are not limited to, the 
following: 
• 
Demography: date of birth, sex, race, ethnicity, height, and weight 
• 
Clinically significant prior non-cancer diagnoses, surgeries, and current medications 
• 
Prior cancer history, current cancer diagnosis, tumor stage at time of diagnosis and at time of study 
screening 
• 
Prior surgical procedure(s), including date, anatomic site, and specific procedure performed; 
including loco-regional liver-directed therapy such as embolization, chemoembolization, 
radiofrequency ablation, etc. 
• 
Current and prior modifiable risk-factors (smoking, alcohol use, including estimated amount and 
duration of use) 
• 
Prior imaging reports, lesion measurements, and/or image reproductions may be requested from 
different periods in the cancer-specific history for a given patient.  
• 
The suspected causal setting in which HCC arose is requested (i.e., a history of hepatitis C (HCV), 
hepatitis B (HBV), or inherited metabolic disorders).   
• 
History of non-alcoholic fatty liver disease (NAFLD), if any 
• 
Smoking and tobacco history 
• 
In addition to AFP levels at baseline, at least one alfa-feto protein (AFP) level from before the 
baseline visit is requested, in order to establish two AFP levels prior to starting sorafenib on study. 
Prior records, radiology reports, or procedure notes may be required in order to verify components of study 
patient history.   
6.2 
Physical Examination 
Complete physical examination including height, weight, blood pressure, heart rate, respiratory rate, 
temperature (oral, axillary or tympanic) and ECOG performance status (Section 16).  In addition, presence 
of encephalopathy and degree of ascites should be assessed so that Child Pugh score can be calculated. 
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 laboratory approved by the sponsor and site Principal 
Investigator.  Please see the Laboratory and Procedure Manual for further details.   
• 
Hematology: CBC including hemoglobin, hematocrit, white blood cell count with 5-part 
differential (automated differential is acceptable), red blood cell, platelet, INR (for prothrombin 
time). 
• 
Blood chemistry: CO2, calcium, phosphorus, magnesium, albumin, glucose, and serum creatinine, 
AST, ALT, lactate dehydrogenase (LDH), alkaline phosphatase, total and direct bilirubin, uric acid, 
total protein and blood urea nitrogen (BUN), 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 
• 
Serum alpha fetoprotein levels 
 
 






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Table 6: Single Sample Pharmacokinetic Sampling Schedule for Phase II / Arm 1 (BBI608) 
Cycle 
Day 
Procedure 
Scheduled Time 
2 
15 
Draw blood sample 
0 hr (predose) 
2 
15 
Patient is administered BBI608 morning dose 
 
Table 7: Single Sample Pharmacokinetic Sampling Schedule for Phase II / Arm 2 (BBI503) 
Cycle 
Day 
Procedure 
Scheduled Time 
2 
14 
Patient is administered BBI503 dose at night 
- 
2 
15 
Draw blood sample 
Any time on Day 15* 
*PK sample can be drawn at any time on Cycle 2 Day 15. Exact time of blood draw and the 
previous night dosing time must be recorded.  
, A total 6 patients for Napabucasin at the RP2D  levelwill have a complete PK assessment using the 
pharmacokinetic draw schedules outlined in Section 6.4.1, Patients assigned to the sorafenib only arm will 
not have PK blood draws obtained. 
Note: 
After the amendment 3 was in effect, Arm 2 in the Phase II portion was closed for enrollment due to BBI503 
portfolio priorities and to increase efforts in enrolling patients on to Arm 1 and 3.  
At the time of the amendment 3 being in effect, there were approximately 10 subjects enrolled in Arm 2 
and approximately 30 patients remains to be the targeted sample size  in each of the two open remaining 
arms, therefore, the total actual sample size in Phase II in the end is projected to be approximately 70 
patients after the amendment 3. 
 
6.5 
Pharmacodynamic Assessments  
Pre-clinical studies conducted at BBI have identified several biomarkers in tumor tissues whose levels 
either increase or decrease upon exposure to BBI608 or BBI503.  Tumor biopsy is an optional component 
of this study.  Provided that the patient has an accessible tumor, an optional tumor biopsy consent form will 
be made available to the patient.  In addition to biopsy, archival tissue will also be collected.   
The goal of the proposed biomarker study is to examine the response of biomarkers in patients treated with 
study drug (either BBI608 or BBI503).  Subject tumor samples will be processed for determination of 
pharmacodynamic markers by histopathology and flow cytometry. 
Tumor biopsy may be collected from patients who consent to the optional procedure during the phase II 
portion of the study – including patients who are randomized to the sorafenib only arm.   
6.5.1 Archival Tissue 
Paraffin-fixed tumor tissue from a previous biopsy or resection is requested of all patients.  Release of tissue 
to BBI for testing is required if tissue is available.  However, patients may still enroll on study if they do 
not have tissue available.  For those with tissue available, tumor blocks are preferred.  If archival tumor 
blocks are not available, then archival tumor-tissue cores are requested.  If tumor cores cannot be made, 20 
glass slides are requested.   
Site study staff and Sponsor-CRAs/monitors will aid in the coordination and shipment of archival tissue 
samples to BBI.  Remaining tissue blocks and/or slides will be returned to sites at the conclusion of testing, 
or at a time requested by the study site.    


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Specific shipping and processing instructions will be detailed in the study Laboratory and Procedure 
Manual.   
6.5.2 Tumor Biopsy 
Biopsy is an optional component of this study. Patients identified by the Principal Investigator as having a 
lesion amenable to biopsy through a minimal to low-risk procedure may be asked to review a separate 
biopsy-component consent form. Of note, image-guided biopsy of internal or visceral lesions may qualify 
as a low-risk procedure.  Patients can refuse the optional biopsy-component of this study and still enroll in 
the main study.  
Patients may consent to one biopsy or to two biopsies.  If the patient consents to two biopsies, a tumor 
biopsy will be collected at some point prior to the administration of the first dose of sorafenib on study, and 
again on Cycle 2, Day 15.  Collection, storage, and shipping of tissue samples will be performed as 
described in the study Laboratory & Procedure Manual.  If a patient consents to only one biopsy, then either 
a baseline/pre-treatment biopsy will be obtained prior to the first dose of sorafenib on study, or an on-
treatment biopsy will be obtained on Cycle 2, Day 15.   
If the tumor biopsy is scheduled for a day other than when blood draws for pharmacokinetics are being 
obtained, then a single blood draw within 30 minutes of the time of the biopsy is required.   


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7 TREATMENT 
7.1 
Sorafenib 
Sorafenib is to be administered at a starting dose of 400 mg twice daily, in accordance with the standard 
starting dose.  Sorafenib will be administered on an empty stomach, either 1 hour prior to a meal or 2 hours 
after a meal.  Sorafenib will be administered according to the product label.  Dose modification is allowed 
according to standard of care.  Patients must qualify for treatment with sorafenib and must be able to obtain 
sorafenib in order to be enrolled on study. 
Sorafenib will be dispensed during the study according to standard of care practices and in accordance and 
local site and manufacturer policies.     
During the phase Ib portion of the study, if sorafenib is discontinued for any reason, administration of study 
drug (either BBI608 or BBI503) may continue per protocol.   
During the phase Ib portion of the study, if study drug (BBI608 or BBI503) administration is permanently 
discontinued for any reason, the patient will be considered to have ended the active treatment component 
of the protocol.  The follow-up phase of the study will begin at that time (see Section 5.10), regardless of 
further treatment decisions made at the discretion of the investigator.     
During the phase II portion of the study, patients may continue to receive BBI608 or BBI503 if they are in 
[phase II Arm 1] or [phase II Arm 2] and if sorafenib is discontinued for any reason.  Patients in [phase II 
Arm 3 ] who discontinue sorafenib will end the active treatment part of the protocol, and will begin the 
follow-up portion of the protocol – including radiologic assessments every 8 weeks (56 days) until disease 
progression is determined per RECIST 1.1 and mRECIST for HCC.   
7.2 
Study Drug 
7.2.1 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 the appropriate number of 
BBI608 80 mg capsules according to the assigned dose cohort and according to the dispensing schedule 
outlined in Section 5.4.  The specific capsule strength of BBI608 for a given site and the associated storage 
conditions will be outlined in the study Laboratory and Procedure Manual. 
Briefly, quantity sufficient for 14 days of BBI608 dosing at the assigned dose level is dispensed on Cycle 
1, Day 15.  Subsequently, quantity sufficient for 28 days of BBI608 dosing at the assigned dose level is 
dispensed on Cycle 2, Day 1 and on Day 1 of each subsequent cycle.    
In addition, on Cycle 1, Day 15, an “extra dose” bottle with 2 days of extra dosing will be dispensed to 
patients for use in case of loss or visit scheduling issues.  Additional “extra dose” bottles can be re-dispensed 
to patients if the original bottles are used.   
7.2.1.1 BBI608 Administration 
BBI608 will be administered orally, twice daily, in continuous, repeating, 28-day cycles, at a starting dose-
level of 160 mg twice daily.  The first dose of BBI608 should be administered shortly after waking in the 
morning.  The second dose should be taken before bedtime, and Approximately 12 hours should separate 
the two BBI608 doses.  BBI608 should not be taken with sorafenib.  At least 2 hours should separate a dose 
of sorafenib from a dose of BBI608.    
BBI608 should be taken before the first dose of sorafenib.   BBI608 should be administered 1 hour prior to 
a meal or 2 hours after.  BBI608 and sorafenib should be taken around the same time every day. 


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An example dosing schedule is provided in the Study Manual. Dose escalation of BBI608 in combination 
with sorafenib will proceed according to the procedures outlined in Section 4. 
7.2.2 BBI503 
BBI503 capsules or tablets will be supplied to the pharmacy at the clinical sites.  BBI503 will be labeled as 
an investigational agent, limited by federal law.  The pharmacist will dispense the appropriate number of 
BBI503 50 mg to 100 mg capsules or 100mg tablets according to the assigned dose cohort and according 
to the dispensing schedule outlined in Section 5.4.  When the capsule supply is depleted, the site will be 
resupplied with the tablet formulation.  The specific type of BBI503 for a given site and the associated 
storage conditions will be outlined in the study Laboratory and Procedure Manual. 
Briefly, quantity sufficient for 14 days of BBI503 dosing at the assigned dose level is dispensed on Cycle 
1, Day 15.  Subsequently, quantity sufficient for 28 days of BBI503 dosing at the assigned dose level is 
dispensed on Cycle 2, Day 1 and on Day 1 of each subsequent cycle. 
In addition, on Cycle 1, Day 15, an “extra dose” bottle with 2 days of extra dosing will be dispensed to 
patients for use in case of loss or visit scheduling issues.  Additional “extra dose” bottles can be re-dispensed 
to patients if the original “extra dose” bottles are used.   
7.2.2.1 BBI503 Administration 
BBI503 will be administered at a starting dose-level of 100 mg Once Daily given in continuous, repeating, 
28-day cycles. BBI503 will be administered before bed and should not be administered at the same time as 
sorafenib.  At least 2 hours should separate a dose of sorafenib from a dose of BBI503.  The total daily dose 
of BBI503 may be divided into sub-doses taken at least 6 hours apart.  Dose escalation of BBI503 in 
combination with sorafenib will proceed according to the procedures outlined in Section 4.   
BBI503 is taken 1 hour prior to meals or 2 hours after.  A dose of BBI503 and a dose of sorafenib should 
be separated by at least 2 hours. 
7.2.3 Investigational Product Accountability 
BBI will provide all study drug (either BBI608 or BBI503) required for completion of this study.  The 
recipient will acknowledge receipt of the drug and will record shipment content and condition.  Damaged 
supplies will be replaced.  Until dispensed to the patients, the study drug will be stored as specified in the 
Pharmacy Manual, in a secure locked area, accessible to authorized personnel only. 
Accurate records of all study drug (either BBI608 or BBI503) dispensed from and returned to the study site 
are to be maintained.  The study site must supply a copy of its 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 will be returned to BBI or designee in the original containers.  
7.3 
Dose Modifications 
The following section outlines the dose-modifications allowed on study for sorafenib and for study drug 
(either BBI608 or BBI503). 
7.3.1 Sorafenib 
The starting dose of sorafenib is 400 mg twice daily, in accordance with the standard starting dose.  Dose 
modification is allowed according to the product label and according to standard of care practices.  
Sorafenib is administered initially as monotherapy for a 2-week run-in period.  The tolerability profile of 


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sorafenib alone should be identified for a given patient during this period, prior to the start of combination 
therapy.   
Dose-modification of sorafenib for non-dermatologic toxicities is allowed.  Dose-modification of sorafenib 
for dermatologic toxicity is as outlined in Table 8 below: 
Table 8: Suggested Sorafenib Dose Modifications for Dermatologic Toxicities in Patients with 
Hepatocellular Carcinoma 
Dermatologic Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 1: Numbness, dysesthesia, 
paresthesia, tingling, painless 
swelling, erythema or discomfort 
of the hands or feet which does 
not disrupt the patient’s normal 
activities 
Any occurrence 
Continue treatment with SORAFENIB and consider 
topical therapy for symptomatic relief 
Grade 2: Painful erythema and 
swelling of the hands or feet 
and/or discomfort affecting the 
patient’s normal activities 
 
 
 
1st occurrence 
Continue treatment with SORAFENIB and consider 
topical therapy for symptomatic relief 
If no improvement within 7 days, see below 
No improvement within 
7 days or 2nd or 3rd 
occurrence 
Interrupt SORAFENIB treatment until toxicity 
resolves to Grade 0–1 
When resuming treatment, decrease SORAFENIB 
dose by one dose level (400 mg daily or 400 mg 
every other day) 
4th occurrence 
Discontinue SORAFENIB treatment 
Grade 3: Moist desquamation, 
ulceration, blistering or severe 
pain of the hands or feet, or 
severe discomfort that causes the 
patient to be unable to work or 
perform activities of daily living 
1st or 2nd occurrence 
Interrupt SORAFENIB treatment until toxicity 
resolves to Grade 0–1 
When resuming treatment, decrease SORAFENIB 
dose by one dose level (400 mg daily or 400 mg 
every other day) 
3rd occurrence 
Discontinue SORAFENIB treatment 
   
7.3.2 Study Drug – BBI608 or BBI503 
The safety profiles of both BBI608 and BBI503 are well established.  The following dose-modification 
guidelines are based on clinical experience to date.   
During the dose-escalation phase of the study, dose-modification of study drug (either BBI608 or BBI503) 
should adhere to the following guidelines: 
• 
For any intolerable Grade 2 or Grade 3 adverse events, the assigned dose of study drug (either 
BBI608 or BBI503) should be held.   
• 
If the adverse event resolves to tolerable levels (must be ≤ grade 2 or at the baseline grade), dosing 
can resume at the assigned dose level with pharmacologic support measures administered.   
o Pharmacologic support measures for each study drug (either BBI608 or BBI503) are 
provided in  Section 7.3.2.1 below.   
• 
If the adverse event takes longer than 5 days to resolve to tolerable levels (≤ grade 2) or to the 
baseline grade, or if the adverse event recurs upon resumed administration despite pharmacologic 
support, the dose may be reduced by one or more dose levels.   


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o If the assigned dose is the first dose-level and dose-reduction is required, a lower level can 
be determined by the Principal Investigator and the medical monitor for the Sponsor.    
o A patient who requires dose-reduction is allowed to increase his or her dose back to the 
assigned dose-level with pharmacologic support. 
• 
Intra-patient dose escalation above the assigned starting dose-level is permitted, provided the 
increased dose-level has been determined safe according to the criteria for dose-escalation and 
determination of dose-limiting toxicity (Section 4.6).   
During the phase II portion of the study, and once RP2D is determined for a study drug (either BBI608 or 
BBI503) in combination with sorafenib, dose-modification can occur according to the following guidelines: 
• 
For Grade 2 or Grade 3 gastrointestinal adverse events, or Grade 2 or Grade 3 fatigue, the assigned 
dose of study drug (either BBI608 or BBI503) may be reduced to a lower dose level with or without 
holding dose (a dose holiday).    
o When restarting study drug administration or when modifying to a lower dose-level, 
supportive pharmacology is to be administered as outlined in Section 7.3.2.1.  
o For a given patient who has reduced his or her dose, and for whom the new dose-level is 
well tolerated, the dose may be increased slowly, as tolerated, with supportive 
pharmacology measures as outlined in Section 7.3.2.1 to a maximum dose of RP2D.     
• 
For all adverse events other than fatigue, nausea, vomiting, anorexia, diarrhea, or cramping, dose 
modification is based on tolerability as follows: 
o Dosing should be held for intolerable Grade 2 or Grade 3 adverse events until the event 
resolves to tolerable levels (≤ Grade 2).   
o If the above criteria are met, dosing can resume at a lower dose level with appropriate 
pharmacologic support measures, if applicable.   
o If the lower dose level is well tolerated, the dose can be increased slowly, as tolerated, with 
supportive pharmacology if indicated, to a maximum dose of RP2D.   
7.3.2.1 Specific Pharmacologic Recommendations - BBI608 and BBI503 
Recommendations for supportive pharmacology for adverse events that can be associated with BBI608 or 
BBI03 administration are outlined in Table 9 below, according to symptom.   


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Table 9: Supportive Pharmacology for Adverse Events Associated with BBI608 or BBI503 
Administration 
Diarrhea & Abdominal Cramping 
 
Nausea, Vomiting, or Anorexia1 
Dicyclomine (e.g., Bentyl): Recommended when 
the predominant issue is cramping or abdominal 
pain 
 
1st line: 5HT3-inhibitorsJD (Ondansetron, 
Palonosetron, Granisetron) 
Diphenoxylate/atropine (Lomotil) 
 
Loperamide (Imodium) 
These 
agents may 
be useful in 
combination 
 
2nd line:  Dexamethasone (Decadron), ideally 
in combination with a 5HT3-inhibitor.  Short 
term use can be very effective 
 
 
Other agents:  NK1 antagonist (e.g. Aprepitant), 
atypical antipsychotic (e.g., olanzapine), 
benzodiazepines (e.g. lorazepam), phenothiazines 
(e.g. prochlorperazine), cannabinoids (e.g., 
dronabinol), and other agents such as 
metoclopromide or scopolamine. 
Hyoscine (Buscopan, Scopolamine, Levsin):  Anti-
spasmodic agents helpful for abdominal cramping 
 
Steroid with limited systemic absorption2 
 
 
1Adapted from NCCN anti-emetic guideline 2017 
2Alimentary tract mucositis reflects mucosal injury across the continuum of oral and gastrointestinal 
mucosal. Expert opinion (2016 ESMO clinical practice guideline recommendations include systemic 
steroid treatment for the management of adverse event observed with use of targeted agents. 
*Decisions on ADR management are at the discretion of the investigator and must adhere with local 
regulatory guidelines  
When study drug (either BBI608 or BBI503) administration is resumed following dose-reduction or a dose 
hold, adverse events that were associated with study drug (either BBI608 or BBI503) administration are 
typically improved.  As such, when a new dose-level of study drug (either BBI608 or BBI503) is tolerated 
for 4 to 7 days and pharmacologic support is administered, the dose can be re-escalated, as tolerated, in 
increments allowed by the capsule or tablet in use (e.g., 80 mg for BBI608 and 50 mg for BBI503 capsule 
or 100mg tablet). The dose can be res-escalated up to either the assigned dose-level (if during dose-
escalation) or up to RP2D (if determined).     
7.4 
Treatment Compliance 
A patient is considered compliant with the study protocol when each component of the assigned protocol 
therapy is taken at a compliance level of greater than 80%.  The components of protocol therapy assigned 
will depend on what study arm the patient is randomized to, and whether the patient is randomized during 
the phase Ib or phase II portion of the protocol.   
Compliance with sorafenib will be calculated using the following equation:  
% Compliance = Number of capsules actually ingested in a given time period
Number of capsules that should have been ingested*
 × 100 
*During the phase Ib portion of the study, the denominator of the compliance equation (the number of sorafenib 
capsules that should have been ingested) refers to the dose of sorafenib administered at the start of combination 
therapy.  During phase II, for patients randomized the sorafenib only arm [phase II Arm 3 ], the denominator of the 
compliance equation will refer to the dose of sorafenib administered on Cycle 1, Day 15.   
Compliance with study drug (either BBI608 or BBI503) will be calculated using the following equation: 
% Compliance = 
Number of capsules or tablets actually ingested in a given time period
Number of capsules or tablets that should have been ingested per dose level × 100 


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7.5 
Blinding 
This is an open label study.  Neither the patient nor the investigator and site staff will be blinded to the 
treatment administered. 
7.6 
Prior Treatment 
Reasonable efforts will be made to determine all prior anti-cancer treatments received by the patient, as 
well as all concurrent medications continuously or occasionally taken at the time of enrollment on study.  
All relevant information must be recorded on the patient's case report form (CRF). All surgical procedures, 
prior chemotherapy, and radiation therapy must be recorded on the appropriate CRF.  In addition to 
recording this information on the appropriate CRF, the information must also be reported to the Sponsor on 
the enrollment form in order to verify eligibility for the study with respect to prior treatments.   
7.7 
Concomitant Medication 
7.7.1 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.  
In addition, the following treatments are allowed: 
• 
Standard therapies for concurrent medical conditions 
• 
Epoetin alfa (Epogen®, Procrit®)  
• 
Hematopoietic growth factors, including filgrastim (Neupogen®) Thrombopoietin (e.g., 
Romiplostim (Nplate®), or other granulocyte colony stimulating factors (G-CSF), are permitted 
Prophylactic anti-emetics and/or anti-diarrheal agents may be administered according to standard 
practice  
• 
Megestrol acetate (Megace®) 
• 
Dexamethasone 
• 
Diphenhydramine 
• 
Cimetidine 
• 
Ranitidine  
• 
Bisphosphonates 
• 
Denosumab 
7.7.2 Prohibited Treatment 
The following medications may not be administered to any patients while they are on study:  
• 
Alternate chemotherapy, hormonal therapy, immunotherapy (not including corticosteroids), and 
non-palliative radiotherapy (radiotherapy with curative intent).   
• 
Other investigational agents 
• 
Immunosuppressive therapies, except for corticosteroids that are: 1) used intermittently in an anti-
emetic regimen, 2) prescribed at a non-immunosuppressive dose for treatment of fatigue and low-
appetite, or 3) prescribed as part of a pre-defined steroid taper for post palliative XRT.      
If no alternative treatment option exists for the prohibited treatments, the situation of individual patient 
should be discussed with medical monitor to decide further course of action. 


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7.7.3 Drug-Drug Interactions 
7.7.3.1 BBI608 
No clinically apparent drug-drug interactions have been identified in patients administered BBI608, 
although a dedicated drug interaction study is currently ongoing in healthy human volunteers.   
Napabucasin is primarily metabolized by the CYP P450 isoform 1A2.  Therefore, caution should be 
exercised with drugs that are strong inhibitors or sensitive substrates of CYP1A2.  
Examples of strong 1A2 inhibitors and sensitive inducers are presented below: 
• 
Strong CYP 1A2 inhibitors: fluvoxamine, ciprofloxacin, enoxacin, zafirlukast 
• 
Sensitive CYP1A2 substrates: alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, 
theophylline, tizanidine  
Possible actions for investigators with patients taking medications as above include: discontinuing the 
medication entirely, continuing the medication and monitoring for adverse effects, and continuing the 
medication at a reduced dose and monitoring for adverse effects.    
7.7.3.2 BBI503 
No clinically apparent drug-drug interactions have been identified in patients administered BBI503, 
although no dedicated studies have specifically evaluated potential interactions.  
 BBI503 was shown to have minimal in vitro inhibitory activity against the individual CYP P450 isoforms 
1A2, 2D6, 2C19, 3A4, and 2C9 with IC50s of ≥10 M for each isoform. In vivo inhibitory activity against 
these isoforms is expected to be > 1000 M, given that the majority of BBI503 (> 99%) is expected to be 
bound to plasma protein. 
In addition, in in vitro studies, BBI503 was not metabolized by any of the CYP P450 isoforms tested (1A2, 
2D6, 2C19, 3A4, and 2C9).   
7.7.3.3 Sorafenib 
Effect of Strong CYP3A4 Inducers on sorafenib  
Rifampin, a strong CYP3A4 inducer, administered at a dose of 600 mg once daily for 5 days in combination 
with a single oral dose of Sorafenib 400 mg in healthy volunteers resulted in a 37% decrease in the mean 
AUC of sorafenib [see US approval label, Clinical Pharmacology Section (12.3)]. Concomitant use of 
strong CYP3A4 inducers (such as carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, 
rifabutin, and St. John’s wort, see Section 7.7.2 as well) is prohibited in this study during the dose-
escalation phase because these drugs can decrease the systemic exposure to sorafenib.  
Effect of Strong CYP3A4 Inhibitors on sorafenib  
Ketoconazole, a strong inhibitor of CYP3A4 and P-glycoprotein, administered at a dose of 400 mg once 
daily for 7 days did not alter the mean AUC of a single oral dose of Sorafenib 50 mg in healthy volunteers. 
However, for this protocol, use of strong CYP3A4 inhibitors is prohibited during the dose-escalation phase 
(see Section 7.7.2). 
Effect of sorafenib on Levels of Other Drugs  
sorafenib 400 mg twice daily for 28 days did not increase the systemic exposure of concomitantly 
administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole 
(CYP2C19 substrate) (see sorafenib product label).  


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Neomycin  
Neomycin administered as an oral dose of 1 g three times daily for 5 days decreased the mean AUC of 
sorafenib by 54% in healthy volunteers that had also been administered a single oral dose of sorafenib 400 
mg. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied (see 
sorafenib product label). 
Drugs that Increase Gastric pH  
The aqueous solubility of sorafenib is pH-dependent, with higher pH resulting in lower solubility. However, 
omeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 5 days, did not result 
in a clinically meaningful change in sorafenib single dose exposure. No dose adjustment for sorafenib is 
necessary when administered with drugs that increase gastric pH. 
 


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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 that are considered to be related to study drug (either BBI608 or BBI503) or that occur after any 
administration of 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 that occur during the clinical trial, commencing with the 
first dose of study drug (either BBI608 or BBI503) and including the protocol-defined post-treatment 
follow-up period (21 Code of Federal Regulations [CFR] §312.64[b]), on designated CRF pages.  AEs that 
occur after signing of the informed consent but prior to the first dose on study will not be reported as AEs*.  
It is also important to record all AEs, whether serious or non-serious, that result in permanent 
discontinuation of the investigational product being studied. 
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. 
*Unless they occurred as the result of a screening test that would not have otherwise been performed as a 
part of standard of care.   
8.1.2 Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical investigational patient who is 
administered a pharmaceutical product; the medical occurrence does not need to have a causal relationship 
to the pharmaceutical product.  An AE can therefore be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, regardless of whether it is 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 rather than laboratory abnormalities are to be recorded when 
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 use accurate AE terminology 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. 
Appropriate CTCAE terms for AEs should be used whenever possible.  If an appropriate CTCAE term is 
not available, then the verbatim term should be documented.   


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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 of the 
investigator and medical monitor for the Sponsor.   
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, that occurs during this investigation or in the 30 days following the last dose of 
study drug, regardless of assessed causality, must be reported to the Sponsor immediately (not to exceed 
24 hours) by telephone, email, or facsimile.  The event must be completely described on the SAE report 
form provided by the Sponsor.  The SAE form should be sent to the Sponsor by email and/or facsimile to 
the contact listed in Table 10 below:   
Table 10: Primary Medical Monitor & Serious Adverse Event Contact 
Matthew Hitron, MD 
Boston Biomedical, Inc 
640 Memorial Drive 
Cambridge, MA 02139, USA 
Telephone:1- (617) 674-6800 ext 8563 
Fax: (617) 674-8662 
Email: mhitron@bostonbiomedical.com 
Emergency Number:  1-508-410-5512 
The SAE should also be entered as an Adverse Event on the Adverse Event CRF, with the fact indicated 
that it was an SAE (checkbox provided on the CRF). 
Follow-up SAE reports are required when there is a significant development in the case.  Examples of 
significant developments include: updates from diagnostic imaging or laboratory testing, new information 
from specialist consultation, or a change in the clinical status of the patient (either improved or worsened).  
Follow-up reports for significant developments are required until the case is considered to be concluded (as 
indicated by resolution of the event such that it is no longer “serious” or as indicated by other means (i.e., 
patient discharge, patient death)).      
 


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9 ASSESSMENT OF ANTI-TUMOR ACTIVITY 
Radiologic images obtained on study will be assessed according to both RECIST 1.1 criteria and the criteria 
outlined in Modified RECIST (mRECIST) Assessment for Hepatocellular Carcinoma.  mRECIST for HCC 
was developed in 2010 by R. Lencioni and JM Llovet to address the poor correlation between conventional 
methods of response assessment and the clinical benefit observed with the then-available treatment 
modalities for HCC.  The modified approach specifically takes into consideration the level of arterial 
enhancement within a HCC lesion when determining response.   
As BBI608 and BBI503 target cancer stem cells, it is not clear whether clinical benefit will be correlated 
with the response assessment made using RECIST 1.1 criteria, or with that made using mRECIST for HCC 
criteria--or correlated with neither set of criteria.  As such, it is recommended that the patient be treated 
clinically and that decisions regarding continuation or discontinuation of protocol therapy be made mainly 
based on clinical assessment; radiologic imaging should inform, but not be the primary determinant of, the 
decision to continue or discontinue therapy.  
Both sets of guidelines are briefly summarized in this section.  For a complete overview, please refer to the 
original publications.  Patient imaging while on study will be categorized according to both RECIST 1.1 
criteria and mRECIST for HCC criteria, when possible.   
In order to be eligible for enrollment, patients must have measurable disease per RECIST 1.1 definitions 
(outlined in Section 9.1.1).  For that lesion to then qualify as measurable according mRECIST, the lesions 
must also show intratumoral arterial enhancement on contrast-enhanced CT or MRI.   
Patients may enroll if they have at least measurable disease per RECIST 1.1.  Please note, however, that 
since exploratory estimates of time to event endpoints such as TTP and PFS will be summarized using both 
methods, all patients should continue to be assessed on-study using both criteria (as progression according 
to mRECIST can be documented even if there is no disease measurable per mRECIST at baseline).   
9.1 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
The definitions and criteria from Response Evaluation Criteria in Solid Tumors [RECIST 1.1, Eisenhauer 
et al. 2009]1 are briefly summarized below.  These criteria should be used to categorize on-study images.   
9.1.1 Basic Definitions for RECIST 1.1 
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. 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <10 mm with 
conventional techniques, <10 mm with spiral CT scan or lymph nodes 10 mm to <15 mm in short axis). 
These small lesions can include bone lesions, ascites, pleural/pericardial effusions, cystic lesions, and 
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. 
• 
External lesions identified on physical exam will be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and when they are ≥ 10 mm when 
measured using calipers.  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. 


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9.1.2 RECIST 1.1 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 contiguous slices of 10 mm or less.  Spiral CT should be performed using a 5-mm 
contiguous reconstruction algorithm. 
• 
All imaging methods should be performed according to institutional standards, and each 
patient should have a consistent method from baseline through the course of the study. 
9.1.3 RECIST 1.1 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 (for lymph nodes, use short-axis) 
will be calculated and reported as the baseline sum LD.  The baseline sum LD will be used 
as the reference from 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. 
• 
Importantly, pre-study images should be assessed by either a member of the clinical 
investigative team at the study site or by a radiologist who is familiar with RECIST 
guidelines.  The image report is not sufficient for identification of lesions per RECIST.  
The images themselves should be assessed at baseline for measurable disease that can 
qualify as target lesions.   
9.1.4 Response Criteria and Classification for RECIST 1.1 
The criteria for response categorization of radiologic imaging assessments per RECIST are highlighted in 
Table 11 and Table 12 below.   


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Table 11: RECIST 1.1 Categorization & Evaluation of Target Lesions 
RECIST Response Category 
Description 
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 
 
Table 12: RECIST 1.1 Categorization & Evaluation of Non-Target Lesions 
RECIST Response Category 
Description 
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  
9.1.5 Evaluation of Overall Response for RECIST 1.1 
The overall response at any time-point is determined from the assessment and categorization of target 
lesions, non-target-lesions, and new lesions as indicated in the Table 13 below: 
 
Table 13: RECIST 1.1 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 per RECIST 1.1 is determined from review of each overall response recorded 
from the start of the treatment until disease progression.   
 


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9.2 Modified RECIST Assessment for Hepatocellular Carcinoma (mRECIST) 
The definitions and criteria from mRECIST (R Lencioni, JM Llovet, 2010) are summarized below.  On-
study images should be categorized according to the definitions and descriptions outlined.   
9.2.1 Basic Definitions for mRECIST 
Only intrahepatic target lesions that are well-delineated and demonstrate arterial enhancement can be 
selected for mRECIST for HCC.  Poorly demarcated lesions or those that show atypical enhancement, 
possibly as a result of previous interventions, cannot be selected as target lesions according to mRECIST.  
In order to qualify as measurable according to mRECIST for HCC, a target lesion must meet the following 
criteria: 
• 
The lesion can be classified as a RECIST measurable lesion (i.e., the lesion can be 
accurately measured in at least one dimension as 1 cm or more). 
• 
 The lesion is suitable for repeat measurement. 
• 
 The lesion shows intratumoral arterial enhancement on contrast-enhanced CT or MRI. 
When measuring the diameter of viable tumor for a potential target lesion according to mRECIST, the 
measurement should not include major intervening areas of necrosis. 
If there are more than two lesions that meet mRECIST criteria for target lesions, then the two largest or 
best demarcated ones should be followed as target lesions, while the others can be considered non-target 
lesions. 
9.2.2 Image Acquisition for mRECIST 
In order to maximize contrast between viable vascularized tumor tissue and non-enhancing necrotic tissue, 
mRECIST requires bi-phasic or tri-phasic imaging techniques.  This protocol specifies bi-phasic or tri-
phasic liver scan.   
In both bi-phasic and tri-phasic scans, the intra-venous contrast material administration should be timed so 
that high-quality arterial-phase imaging is obtained throughout the liver on the first run.  Subsequently, on 
the second run, high-quality portal venous-phase imaging should be obtained.  In tri-phasic scans, delayed 
imaging obtained in the equilibrium phase.   
9.2.3 Response Criteria and Classification for mRECIST 
The response categorization of target and non-target lesion observations according to mRECIST is 
summarized in Table 14 and Table 15 below.   


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Table 14: mRECIST Categorization & Evaluation of Target Lesions  
RECIST Response Category 
Description 
Complete Response (CR): 
Disappearance of any intratumoral arterial enhancement in all 
target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of viable 
(enhancement in the arterial phase) target lesions, taking as 
reference the baseline sum of the diameters of target lesions 
Progressive Disease (PD): 
An increase of at least 20% in the sum of the diameters of viable 
(enhancing) target lesions, taking as reference the smallest sum 
of the diameters of viable (enhancing) target lesions recorded 
since treatment started 
Stable Disease (SD): 
Any cases that do not qualify for either partial response or 
progressive disease 
 
Table 15: mRECIST Categorization & Evaluation of Non-Target Lesions 
RECIST Response Category 
Description 
Complete Response (CR): 
Disappearance of intratumoral arterial enhancement 
Stable Disease (SD): 
Persistence of intratumoral arterial enhancement in one or more 
non-target lesions 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
For further guidance and details on specific clinical scenarios, please consult Lencioni and Llovet, 2010. 
9.2.4 Evaluation of Overall Response in mRECIST 
The determination of overall response at a given time-point for mRECIST is identical to the determination 
of the overall response at a given time-point in RECIST 1.1, and is highlighted again in Table 16 below.   
Table 16: mRECIST 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 is determined from all overall responses recorded from the start of the treatment 
until disease progression. 


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9.3 Assessment of New Lesions  
As outlined in Table 13 and in Table 16, the appearance of a new lesion by either RECIST or mRECIST 
declares progression as the overall response at that imaging time-point regardless of the response assessed 
in target or non-target lesions.  Given the significant impact this has on determination of time-to-progression 
endpoints, care must be taken to ensure new lesions are recorded accurately.  
Determination of new lesions in HCC can often be complicated because of the   underlying diagnosis of 
cirrhosis in most patients.  As such, a newly appearing lesion must meet certain conditions in order to 
qualify as a “New Lesion” for the purpose of response assessment.  These conditions for both RECIST 1.1 
and for mRECIST are outlined below in Section 9.3.1 and Section 9.3.2.  
9.3.1 New Lesions in RECIST 1.1 
New lesions should be unequivocal and not attributable to differences in imaging modality or techniques. 
Findings from processes not directly related to tumor progression should also be excluded.  
If a new lesion is equivocal, or uncertain as to etiology, protocol treatment should continue until a 
subsequent radiologic image is obtained at least 4 weeks later. If repeat imaging confirms the original 
diagnosis of new lesion, then the original scan date should be used for the radiologic diagnosis of 
progressive disease. 
9.3.2 New Lesions in mRECIST for HCC 
The approach to a potential new lesion when assessing response according to mRECIST for HCC is 
outlined below: 
• 
A newly detected hepatic nodule will be classified as HCC if its longest diameter is at least 1 cm 
and the nodule shows the typical vascular pattern of HCC on dynamic imaging.  
• 
Liver lesions larger than 1 cm that do not show a typical vascular pattern can be diagnosed as 
HCC if repeat radiologic imaging shows at least 1-cm-interval growth. 
• 
If repeat imaging confirms the original diagnosis of new lesion, then the original scan date should 
be used for the radiologic diagnosis of progressive disease. 


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10 PLANNED STATISTICAL METHODS 
10.1 Analysis Populations 
The study populations for subsequent analyses below will be defined for phase Ib, phase II, and overall.   
Enrolled Patients: A patient is considered enrolled upon receiving the first dose of 
sorafenib on Cycle 1, Day 1. 
Study Drug Safety Population: Defined by all patients receiving at least one dose of study drug 
(either BBI608 or BBI503). 
Pharmacokinetic Population: Defined as those patients who have completed all pharmacokinetic 
assessments.   
Dose-Escalation Population: Patients are considered evaluable for the determination of dose-
escalation if they: 
a) Experience dose-limiting toxicity (DLT) 
b) Complete 28-days of combination dosing at the assigned 
dose-level 
Population Evaluable for 
Response: 
The evaluable population is those patients who have received at 
least one cycle of study drug (either BBI608 or BBI503) and who 
have had at least one objective disease assessment following the 
initiation of therapy. 
Intent to Treat Population: All randomized patients, regardless of receiving a dose of 
sorafenib or study drug.  
10.2 Phase Ib Randomization  
Randomization is appropriate for this portion of the study as, once all inclusion and exclusion criteria for 
the study have been met, there are no absolute or relative medical contraindications specific to either 
BBI608 or BBI503.  The adverse event profiles for the agents are similar and there is no difference between 
the agents at this time with respect to the balance of relative clinical risk and potential clinical benefit of 
combination therapy with sorafenib.  Patients who meet all inclusion and exclusion criteria will be eligible 
for randomization.   
A central randomization will be performed whereby patients will be assigned to Arm 1 (BBI608 plus 
sorafenib) or Arm 2 (BBI503 plus sorafenib) using block randomization.  Each block will be considered a 
cohort with 3 subjects on Arm 1 and 3 subjects on Arm 2.  After the first cohort for an Arm is complete, 
the dose level for the next cohort will be determined by the dose escalation rules.  It is therefore possible 
that Arm 1 and Arm 2 will have different dose levels for a given cohort.   
Eligible patients will be assigned to a study arm according to the first available patient slot on the 
randomization list (determined a-priori).  Slots on the randomization list will be available or unavailable 
based on the status of dose-escalation for a given study arm.   


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10.3 Phase II Randomization 
Approximately 90 patients (30/arm) were planned to be randomized in a 1:1:1 ratio into three treatment 
arms: Arm 1 (sorafenib plus BBI608), Arm 2 (sorafenib plus BBI503), and Arm 3 (sorafenib alone) before 
Amendment 3 was in effect. After amendment 3 was in effect, Arm 2 in the Phase II portion was closed for 
enrollment and randomization is now conducted in a 1:1 ratio in the two remaining treatment arms: Arm 1 
and Arm 3. The targeted sample size remains 30 for Arm 1 and 30 for Arm 3. There were approximately 
10 subjects already enrolled in Arm 2 by the time amendment 3 was in effect. Therefore, the total actual 
sample size in Phase II in the end is projected to be approximately 70 patients after amendment 3.  
10.4 Primary and Secondary Study Objectives 
10.4.1 
Primary Objectives 
Phase Ib: 
The primary objective of the phase Ib portion of this study is to determine the safety and tolerability of each 
study drug in combination with sorafenib in order to define a recommended phase II dose for BBI608 plus 
sorafenib as well as for BBI503 plus sorafenib.  Safety analysis is defined further in Section 10.5.     
Phase II: 
The primary objective of the phase II portion of this study is to evaluate the tolerability, safety. and 
preliminary anti-tumor activity in patients with advanced hepatocellular carcinoma randomized to receive 
treatment with sorafenib in combination with BBI608, sorafenib in combination with BBI503*, or sorafenib 
alone, with BBI608 and BBI503 administered at their respective RP2D dose levels for combination 
administration with sorafenib which were determined during phase Ib.   
*Once the amendment 3 is in effect, Arm 2 in the Phase II portion will be closed for enrollment. 
10.4.2 
Secondary Objectives 
Other key study objectives include the evaluation of pharmacokinetics and pharmacodynamics (when 
biopsy is possible), and the evaluation of preliminary anti-tumor activity of each agent in combination with 
sorafenib.  The activity of sorafenib alone will also be evaluated in this study.     
Preliminary anti-tumor activity will be explored using different efficacy parameters.  Efficacy parameters 
which involve disease progression as an endpoint will be generated twice: once using disease progression 
as defined by RECIST 1.1, and again using disease progression defined by mRECIST for HCC.  This is 
because the two response evaluation criteria are different, and will produce different results for a given 
efficacy parameter.  The data accumulated on this trial will help to determine whether the use of one 
approach over the other may be preferred in future trials of either BBI608 or BBI503 in hepatocellular 
carcinoma.   
Proportional efficacy parameters will be defined for both phase Ib, phase II, and combined according to 
study arm.  The following parameters will be calculated for all randomized patients and for patients 
evaluable for response: Disease control rate (DCR), defined as the proportion of patients with best response 
of complete response (CR), Partial Response (PR), or stable disease (SD); and Objective response rate 
(ORR), defined as the proportion of patients with a documented complete response (CR) or partial response 
(PR).  As above, DCR and ORR will be defined according to RECIST 1.1 and, in a separate analysis, 
according to mRECIST for HCC.     
The following time-to-event parameters will also be evaluated: time-to-progression (TTP), defined as the 
time from initiation of therapy until disease progression; and progression free survival (PFS) defined as 
time from the initiation of therapy until disease progression or death from any cause.  Also, as above, disease 
progression in both PFS and TTP will be defined according to both RECIST 1.1 and, in a separate analysis, 


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according to mRECIST for HCC criteria.  Estimates for PFS and TTP will be generated using  Kaplan-
Meier curves.     
Since BBI608 and BBI503 both affect cancer stem cells, Disease-Specific Survival (DSS) and overall 
survival (OS) will also be evaluated.  DSS is defined as the time from initiation of therapy until death from 
hepatocellular carcinoma.  Overall survival is defined as time from initiation of therapy until death from 
any cause.  Estimates of DSS and OS for each cohort will be displayed using Kaplan-Meier curves.   
Other evidence for anti-tumor activity will be evaluated on an exploratory basis and will be summarized 
using descriptive statistics or graphics.  These may include but are not limited to: a summary of tumor 
marker values over time, a description of the duration of response or duration of disease control, and 
summaries of the proportion with PFS, TTP, DSS, and OS, at 3, 4, 6, and/or 12 months.   
The potential effects of baseline demographic, clinical, and biologic factors on study outcomes will also be 
explored.  Examples include evaluating the effect of baseline performance status, comorbidities, estimated 
portal pressure, or plasma IGF-1 levels on measures of clinical activity such as time to progression or 
progression free survival.   
10.5 Determination of Sample Size 
Phase Ib:  
The sample size for this study was determined by clinical rather than statistical considerations.  With cohort 
sizes of three to six patients during phase Ib, if the true underlying rates of DLT at a given dose-level are 
0.1, 0.2, 0.3, 0.4, and 0.5, there will be 91%, 71%, 49%, 31%, and 17% chances, respectively, of escalating 
to the next full dose. 
Phase II: 
There are no statistical hypothesis testing and the sample size is considered to be clinically adequate to 
assess tolerability, safety, and preliminary anti-cancer activity of study drug of interest.  Estimation and 
95% confidence intervals will be provided for the proportion of patients with grade 3 adverse events by 
treatment, as well as for the proportion of patients that are alive and progression free 4 months (PFS-4) after 
randomization for each arm. Other anti-cancer activity parameters will also be estimated 
10.6 Safety Analysis 
Safety and adverse events will be summarized for all enrolled patients in the phase Ib portion, phase II 
portion, and for the study overall.  In addition, all patients receiving at least one dose of study drug (either 
BBI608 or BBI503) will be considered in the study drug safety population.  Safety and adverse events will 
be summarized for the study drug safety population of phase Ib, phase II, and overall.   
During the phase Ib portion of the study, adverse events will be summarized by dose-level and overall by 
arm.  The numbers of patients enrolled, number with DLT, and number evaluable for determination of dose-
escalation at each dose-level by arm will be reported.  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. 
Adverse events will be graded according to the NCI CTCAE, version 4.0.  The incidence of adverse events 
will be evaluated for each cohort.  Patients will be followed for adverse events for at least 30 days after the 
last dose of study drug (either BBI608 or BBI503), or until they have recovered from all related study drug 
(either BBI608 or BBI503) adverse events.  
Safety and adverse events will be reported by study arm for the intent to treat population and for all enrolled 
patients during the phase II portion of the study.   


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10.7 Pharmacokinetics, Pharmacodynamics and Exposure-Response Variables 
Exposure-Response evaluations on this study will be exploratory in nature.  Descriptive summaries may be 
generated about plasma levels of study drug (either BBI608 or BBI503) basic demographic variables, 
clinical and biologic factors, pharmacodynamic parameters from biopsy and/or PBMC analysis, and safety 
and efficacy outcome data. 


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11 QUALITY CONTROL AND ASSURANCE 
The study will be initiated and conducted under the Sponsorship of BBI.  The clinical supplies of study 
drug (either BBI608 or BBI503) 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 the subject (for whom the deviation 
from the protocol was affected) is to continue in the study.  The case records will describe both the details 
of and rationale for the protocol deviation. 
11.2 Registration and Enrollment 
This is an open-label study.  BBI will allocate enrollment slots to clinical sites according to random 
assignment of currently available openings in dosing cohorts for both agents.  BBI should be notified as 
soon as a subject qualifies for entry into the protocol.  Subjects will be registered by faxing or emailing a 
completed enrollment form to BBI or its designee within 7 days prior to the first drug administration.  The 
subject will be enrolled into the study when the subject receives the first dose of protocol therapy.  
Registration and enrollment forms as well as faxing/emailing instructions will be provided.  The site is 
required to maintain a log of all subjects who sign consent, and the log must indicate whether the subject 
was enrolled (received a dose of protocol therapy).  The reason for disqualification should be noted in the 
log. 
11.3 Removal, Replacement, or Early Withdrawals of Subjects 
If a subject exits the study prior to receiving four weeks of study drug (either BBI608 or BBI503) for 
reasons other than a DLT, and is not evaluable for dose-escalation then another subject may be enrolled to 
replace the patient in order to fully evaluate safety and tolerability of a given dose-level.  
If a subject exists the study after receiving four weeks of study drug (either BBI608 or BBI503), but before 
receiving an on-study objective disease assessment (and is therefore not evaluable for response), then that 
subject may be replaced.   


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12 GCP COMPLIANCE AND ETHICAL CONSIDERATIONS 
12.1 Institutional Review Board 
 The protocol, any protocol modifications, the 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 BBI or its designee and made 
available during an inspection by loco-regional regulatory agency inspectors.  The Investigator will submit 
to BBI: 
- 
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 patients may be enrolled until the IRB has given written approval of the protocol and informed consent 
and BBI 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 
- 
Submit progress reports to the IRB (if required) and request study review during the course 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 
 
- 
Provide the IRB with a final report on the study within 3 months of study completion 
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 a written and dated approval/favorable 
opinion from the IRB/IEC for the trial protocol/amendment(s), a written informed consent form, patient 
recruitment procedures (e.g., advertisements) and written information to be provided to patients. 
Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to implementation, 
except when the modification is needed to eliminate an immediate hazard(s) to patients. 
 
12.3 Informed Consent and Permission to Use Private Health Information 
The Investigator, or designee, is responsible for the content of the informed consent form, but the content 
must be submitted and approved by BBI 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 


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(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.  
The informed consent form 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, options other than 
study participation, 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. 
Before enrolling a subject into the study, the Investigator or designee must explain to the patient subject 
that for evaluation of study results, the subject’s private health information obtained during the study may 
be shared with the study Sponsor, regulatory agencies, and ECs/IRBs. 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. 


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13 STUDY MANAGEMENT 
13.1 Amendments to the Protocol 
Once the protocol has been approved by the IRB, the Investigator will not modify it without obtaining the 
prior concurrence of BBI.  In turn, BBI 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.  BBI will submit 
protocol modifications to the regional regulatory authority. 
13.2 Investigator Brochure and Information Materials 
Before the study begins, the Investigator will receive an Investigator’s Brochure describing all known 
contraindications, warnings, precautions, and adverse reactions associated with the administration of the 
study drug.  If such information is revised while the study is in progress, the brochure will be amended or 
revised, and Boston Biomedical will provide the most current version to the Investigator. 
13.3 Pre-investigational Documents 
Prior to the shipment of the study drug(s), the Investigator will supply BBI with the following: 
- 
A signed Investigator Clinical Research Agreement 
- 
Current curricula vitae and copy of current medical license for the Principal Investigator and Sub-
Investigators 
- 
A completed Delegation of Authority* document, signed by the Principal Investigator.   
- 
A completed financial disclosure form for all personnel listed on the Delegation of Authority 
document.     
- 
Signed and dated protocol signature page by the Principal Investigator 
- 
A copy of the approval for this protocol from the IRB  
- 
A copy of the approval for the informed consent from the IRB  
- 
A copy of the IRB-approved informed consent 
- 
Evidence of laboratory certification and a list of laboratory normal ranges for all laboratories  
- 
A list of the IRB members and the member occupations and affiliations 
- 
Written verification that the IRB is duly constituted or the General Assurance Number 
For clinical sites in the US, Form FDA 1572 must be completed.  The form must list the Principal 
Investigator and sub-investigators, all laboratories where study labs will be performed, and the local ethics 
authority responsible for reviewing the clinical protocol and informed consent form.   
*The Delegation of Authority document lists the site personnel and the specific study tasks that they will be 
responsible for.  The Delegation of Authority document may be updated during the course of the clinical trial.  The 
update must be signed by the Principal Investigator for the trial and the document submitted to the Sponsor.  A template 
document and legend will be supplied by the Sponsor. 
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.  BBI will provide forms to facilitate the 
inventory control.  These forms must be used unless the Investigator has previously established a system 
that complies with loco-regional regulations and is approved by BBI.  The study drug must be dispensed 
only to the institutions(s) specified on the appropriate loco-regional regulatory documentation. 


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13.5 Disposition of Used and Unused Study Drug 
Upon completion or termination of the study and after inventory by a BBI monitor or designated 
representative, all unopened drug is to be returned to BBI in the original containers.  All used vials will be 
retained until released for destruction by the BBI monitor.  Unopened returned drug, with completed BBI 
forms for return shipment, should be shipped as instructed by the Sponsor. 
13.6 Study Records 
BBI will provide the Investigator with drug shipment records, CRFs designed to collect the data specified 
for each individual, and other forms as necessary.  CRFs provided in electronic format will be United States 
CFR 21 part 11 compliant.   
The Investigator and/or institution is required to prepare and maintain these forms in accordance with local, 
regional, and national regulations, and to sign, date, and return them to the Sponsor. 
Upon the request of authorized BBI or appropriate regulatory agency personnel, the Investigator will make 
available for inspection subject source documents (i.e., 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 BBI. 
BBI 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 regional regulatory authorities or 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 BBI personnel or by a contractor acting on behalf of BBI, 
or by a regulatory agency (such as the FDA or Health Canada). 
13.10 Case Report Form (CRF) Completion 
A set of CRFs or eCRF access will be provided for each study subject.  All forms must be filled out in non-
erasable ink or typed (or entered electronically).  Training will be provided in the case of electronic CRFs.  
The Investigator will sign and date each CRF as indicated.   
Correction of data on a CRF will depend on whether paper or electronic CRFs are utilized.  Paper CRF 
corrections 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 


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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. 
Corrections to electronic CRFs will be audit-tracked in compliance with United Sates CFR 21 part 11.   
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 BBI. 
13.12 Final Study Report 
At the conclusion of the study, after the data are analyzed, BBI 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, to regional regulatory authorities, and to other government agencies if 
requested. 
All information disclosed to the Investigator(s) by BBI 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 BBI or any other party to retain such information in confidence. 
13.14  Publication 
BBI 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 that such 
publication does not disclose any Confidential Information or trade secrets of BBI (other than the Clinical 
Data).  If the Study is conducted as part of a multi-center protocol, Principal Investigator agrees not to 
independently publish his or her findings except as part of an overall multi-center publication, unless 
specifically approved in writing by BBI.  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 BBI a copy of the item to be submitted for publication or presentation.  Upon 
reasonable request by BBI that is made 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, BBI shall have the right to require the Principal Investigator to delete from any 


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publication or presentation any Confidential Information (other than the Clinical Data) of BBI and to require 
that any publication or presentation concerning the Study to acknowledge the Sponsor’s support. 
13.15 Research Outside the Terms of this Protocol 
BBI 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 BBI.  The nature and results of any such procedures must be recorded and reported by a 
method agreed between BBI and the Investigator.  The consent of the subjects must be obtained before any 
such procedures are undertaken. 
The investigative drug provided to the Investigator for use under this protocol may not be used for any other 
purpose, including another study, compassionate use, or personal use. 
 






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6 For patients in Phase II, C3D15 visits (and Day 15 visits of each subsequent cycle) need not be in person.  In this case, the patient should be contacted by phone. 
Vital signs and weight need not be taken. 
7 Optional tumor biopsy may be performed at any time between the screening visit and administration of the first sorafenib dose on Cycle 1 Day 1. 
8 If a patient discontinues protocol therapy due to radiologic progression of disease, an End of Study imaging assessment is not required 
9 Patients who are identified at the EOS visit as having persistent adverse events related to study drug (either BBI608 or BBI503) should continue to be followed 
on a monthly basis (or more frequently if clinically indicated) until resolution of study drug-related adverse events or until the AEs are deemed irreversible.  
10 For ARM 2 only-BBI503 will be administered in the morning ONLY on C1D15 and in the evenings thereafter. Once the amendment 3 is in effect, Arm 2 in 
the Phase II portion will be closed for enrollment.  
11 for phase II 12 Lead ECG should be performed pre dose BBI608 on C1D15 and after dose of  BBI608 on C2D15.  
 
 
 
 
 
 
2 


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16 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. 
 
 
 
 
 
 
 
 




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18 INVESTIGATOR’S SIGNATURE 
Study Title: 
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Sorafenib or BBI503 in Combination with Sorafenib 
in Adult Patients with Hepatocellular Carcinoma 
Study Number: 
BBI608-503-103HCC 
I have read the protocol described above. I agree to comply with all applicable regulations and to conduct 
the study as described in the protocol.  
 
Printed Name: _____________________________________ 
 
 
 
Signature: _________________________________________Date: ____________________ 
 
 
 
 
 


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19 REFERENCES 
[Please find a list of 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)).]  
 
Boman BM, and Wicha MS. (2008) “Cancer stem cells: a step toward the cure.” J Clin Oncol. 26(17): 2795-2799. 
 
Bruix J, Llovet JM, et al. (2012) “Efficacy and safety of sorafenib in patients with advanced hepatocellular 
carcinoma: subanalyses of a phase III trial” J Hepatol. 57(4):821-9.  
 
Bruix J and Sherman M (2011) “Management of hepatocellular carcinoma: an update.” Hepatology 53(3): 1020-1022. 
 
Clevers H (2011) “The cancer stem cell: premises, promises and challenges.” Nature Med.17(3): 313-319. 
 
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