Clinical trial NCT02315534
Conditions: Glioblastoma
Keywords: GBM Malignant Glioma
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2015-03-01; Completion date: 2019-06-24
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open label, multi-center, phase 1 safety run-in and phase 2 study of BBI608 in combination with temozolomide in patients with recurrent or progressive glioblastoma who have not received prior bevacizumab therapy.

Detailed description:
In arm A, patients who are candidates for surgical resection will receive BBI608 as monotherapy prior to resection, followed by post-operative BBI608 administered in combination with temozolomide. In arm B, patients who are not candidates for surgical resection will receive BBI608 administered orally, daily, in combination with temozolomide.

In the phase 1/dose-limiting toxicity (DLT) cohort portion of this study, pharmacokinetics will be evaluated for both arms A and B. Pharmacodynamics will be evaluated in all patients who undergo surgical resection.

Arms: arm 1: Patients for whom surgery is recommended as part of treatment for recurrent Glioblastoma. arm 2: Patients for whom surgery is not recommended as part of the treatment for recurrent Glioblastoma.
Interventions: intervention 1: BBI608 intervention 2: Temozolomide
Intervention descriptions: intervention 1: In arm A, BBI608 will be administered at the recommended Phase 2 dose (RP2D) twice daily for 7(±2) days prior to planned surgical resection or biopsy of recurrent GBM. Upon the clinical recovery of the patient and at a time between 15-28 days after surgery, BBI608 will be administered orally, daily, each day of a 28 day cycle in combination with temozolomide.

In arm B, patients who are not candidates for surgical resection will receive BBI608 administered orally, daily, each day of a 28 day cycle at the RP2D in combination with temozolomide. intervention 2: Temozolomide (TMZ) will be administered orally, once daily, at a dose of 150 mg/m\^2 daily on days 1 through 5 of each 28-day study cycle. The dose of temozolomide can be increased to 200 mg/m\^2 as per standard TMZ dosing guidelines for patients who complete at least one cycle at 150 mg/m\^2.

Protocol documents:
Prot_000.pdf: 
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TITLE:
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Temozolomide for Adult Patients with Recurrent 
or Progressed Glioblastoma
PROTOCOL NUMBER:
BBI608-201GBM
STUDY DRUG:
BBI608
SPONSOR:
Boston Biomedical, Inc.
640 Memorial Drive
Cambridge, MA 02139
Telephone:(617) 674-6800
Fax:  (617) 674-8661
MEDICAL MONITOR:
Waldo Ortuzar, MD
SAFETY FAX:
(617) 674-8662
SAFETY CONTACT:
(617) 674-6800 x 8722
DATE OF PROTOCOL:
September 23, 2014
DATE OF AMENDMENT:
March 9, 2017
AMENDMENT:
3
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Boston Biomedical, 
Inc.  Any unauthorized use or disclosure of such information without the prior written authorization of Boston 
Biomedical, Inc. is prohibited.
Waldo Ortuzar, MD
September 23, 2014
(617) 674-6800 x 8722
(617) 674-8662
Telephone:(617) 674-6800
Fax:  (617) 674-8661
Boston Biomedical, Inc.
640 Memorial Drive
Cambridge, MA 02139


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SYNOPSIS 
Study Title:
A Phase Ib/II Clinical Study of BBI608 in Combination with Temozolomide for 
Adult Patients with Recurrent or Progressed Glioblastoma 
Study Number:
BBI608-201GBM
Study Phase: 
Ib/II
Study Drug
BBI608, a novel investigational small molecule anticancer drug that targets  
cancer stem cells 
Primary Objectives: 
The primary objective of this phase Ib/II study is to determine the safety, 
tolerability, and preliminary anti-cancer activity of BBI608 in combination with
temozolomide (TMZ) in adult patients with recurrent or progressive 
glioblastoma (GBM) who have not received prior treatment with bevacizumab. 
Patients who are eligible for further surgical resection will be enrolled into Arm 
A.  Patients who are not eligible for further resection will be enrolled into Arm 
B.
The primary efficacy endpoint will be progression-free survival at 6-months 
(PFS-6), defined as the proportion of patients who have survived without 
objective disease progression per RANO criteria for at least 6 months after 
enrollment. Secondary endpoints will include median progression free survival 
(PFS), overall survival (OS), disease control rate (DCR), and objective response 
rate (ORR) (when applicable).
Secondary 
Objectives:
To determine the pharmacokinetic profiles of BBI608 and of BBI608 plus TMZ 
when administered to this population.
To determine the pharmacodynamics (biomarkers) of BBI608 in resected 
glioblastoma tissue (when applicable).
Study Design:
This is an open-label, multi-center, phase Ib/II study of BBI608 administered in 
combination with TMZ to patients with recurrent or progressive GBM who have 
not received prior bevacizumab therapy.
ARM A: Patients who are candidates for surgical resection will receive BBI608 
as monotherapy prior to resection, followed by post-operative BBI608 
administered in combination with TMZ.
BBI608 will be administered at a dose-level of 480 mg twice daily for 7 (±2)
days prior to a planned surgical resection or biopsy of recurrent GBM.  BBI608 
will be discontinued immediately prior to the surgical procedure and will remain 
discontinued pending clinical post-operative recovery of the patient.  
Upon the clinical recovery of the patient and at a time between 15-28 days 
following surgery, BBI608 will be administered orally, daily, in combination 
with temozolomide that is administered at 150 mg/m2 for days 1 through 5 of 
each 28 day cycle The dose of temozolomide can be increased to 200 mg/m2 as 
per standard TMZ dosing guidelines for patients who complete at least one cycle 
at 150 mg/m2.  The initial dose of BBI608 will be 480 mg twice daily. Dose 
adjustment is allowed.  


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Pre-Operative Period
BBI608 monotherapy
S
U
R
G
E
R
Y
/
B
I
O
P
S
Y
Post-Operative Period
BBI608 with TMZ
BBI608 will be 
administered orally, daily, 
at a dose-level of 480 mg 
twice daily for 7 (±2) days
prior to a scheduled 
resection for recurrent 
GBM.    
BBI608 will be administered orally, 
daily, at a dose-level of 480 mg twice 
daily in combination with TMZ 150 
mg/m2 that is administered on days 1
through 5 of each 28-day cycle. Cycles 
will repeat until disease progression or 
another discontinuation criterion is met.
Approximately 7 (±2) days
Begins between 15-28-days after surgery
ARM B: Patients who are not candidates for surgical resection will receive 
BBI608 administered orally, daily, in combination with temozolomide 150 
mg/m2 that is administered on days 1 through 5 of each 28-day cycle.  The dose 
of temozolomide can be increased to 200 mg/m2 as per standard TMZ dosing 
guidelines for patients who complete at least one cycle at 150 mg/m2.  The 
initial dose of BBI608 will be 480 mg twice daily. Dose adjustment is allowed.
In the phase Ib/DLT cohort portion of this study, for both Arms A and B, 
pharmacokinetics will be evaluated on Day 1 and Day 5 of combination therapy 
with BBI608 and TMZ.  Pharmacodynamics will be evaluated in all patients 
who undergo surgical resection. 
For patients in Arm A during the run- in period with BBI608 monotherapy, the 
same DLT rules as for the combination therapy will apply.  Enrollment will be 
held if ≥2 patients are unable to undergo resection due to DLTs. Enrollment will 
also be held if  ≥ 2 patients have an unexpected surgical complication.
Initial enrollment will be to a 6-patient safety cohort in each arm.  These patients 
will be evaluated for the occurrence of DLT during the first 28 days of 
combination treatment with BBI608 and TMZ.  If DLT is observed in ≥ 2 of 6 
patients evaluable for DLT, the initial dose of BBI608 for all patients in that arm
will be reduced to the next lower dose level of 240mg twice daily and an 
additional 6-patient safety cohort will be enrolled at that dose-level and 
evaluated for DLT as above.  Enrollment will continue at a dose-level at which 
≤ 1 of 6 patients experiences DLT.   Dose modification is allowed according to 
the standard schedule for BBI608. 
It is expected that up to 30 patients (including those enrolled to the DLT 
evaluation cohorts) will be enrolled in each arm.
For all patients on study, tumor assessments will be performed at eight-week 
intervals or as clinically indicated.  Disease status will be assessed by contrast-
enhanced magnetic resonance imaging (MRI) of the brain. 
Progression Free Survival will be assessed from the date of enrollment until 
objective disease progression or death. Tumor response and progression will be 
evaluated using RANO criteria.  Patients who are enrolled in Arm A but who do 
not undergo surgical resection will be considered evaluable for tumor response
utilizing the same assessment criteria as employed for patients in Arm B. All
patients will be followed for disease progression and included in time-to-event 
analyses.
Patients will continue treatment with BBI608 and TMZ until the investigator has 
determined that they are no longer clinically benefiting due to progression of 


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disease, or unacceptable toxicity, or until another discontinuation criterion is 
met.  Treatment with BBI608 as monotherapy can continue if TMZ is 
discontinued for any reason. Also, the investigator may continue BBI608 in 
combination with TMZ or BBI608 monotherapy after the initial demonstration 
of radiological progression and in the absence of intolerable toxicities, 
performance status decline, worsening of disease related symptoms, 
radiographical findings that would warrant acute intervention and no ongoing 
severe toxicities that may be related to BBI608.  The patient will also get repeat 
tumor assessments after 4-6 weeks.  Treatment with BBI608 (with or without 
TMZ) will continue until unacceptable toxicity, further disease progression 
(clinical or radiological), or another discontinuation criterion is met.
Safety will be evaluated for the duration of the study. Adverse events will be 
documented using the current version of the NCI CTCAE (v 4.0).  
Study Populations: 
This study will enroll patients with histologically confirmed glioblastoma 
(GBM) at first recurrence of disease following front-line therapy.
Patients must have received prior treatment with standard first line therapy for 
GBM, including maximal surgical resection and postoperative external-beam 
radiotherapy. Concurrent chemoradiation with TMZ is allowed but not 
mandatory.
Patients are eligible for enrollment if they have unequivocal evidence of tumor 
recurrence/progression by MRI a minimum of 12 weeks following completion 
of radiation therapy or TMZ-Radiotherapy. Patients who have received prior 
bevacizumab or other anti-VEGF agents are not eligible to enroll.  
Baseline MRI should be performed within 28 days prior to enrollment. 
Other key inclusion criteria include ECOG status of 0-1 (KPS ≥ 70%) and 
adequate bone marrow, hepatic, and renal function at baseline.
Test Product, Dose, 
and Mode of 
Administration: 
BBI608 will be administered orally, twice-daily, at an initial dose-level of 480 
mg twice daily.  The first dose should be administered in the morning and the 
second dose should be administered approximately 12 hours later.  The doses 
should be administered with fluids, one hour prior to or two hours after meals.
The BBI608 dose can be modified according to the following schedule:
Dosing Level
Description
Initial Dose
480 mg twice daily   (960 mg total daily)
Modification Level – 1
240 mg twice daily   (480 mg total daily)
Modification Level – 2
80 mg twice daily     (160 mg total daily)
Modification Level – 3
80 mg once daily
(80 mg total daily)
TMZ will be administered orally, once daily, at a dose of 150 mg/m2 daily on 
days 1 through 5 of each 28-day study cycle. The dose of temozolomide can be 
increased to 200 mg/m2 as per standard TMZ dosing guidelines for patients who 
complete at least one cycle at 150 mg/m2.
Duration of 
Treatment: 
For an individual patient, treatment with BBI608 and TMZ will continue until 
unacceptable toxicity, disease progression (clinical or radiological), or another 
discontinuation criterion is met.  Treatment with BBI608 as monotherapy can 
continue if TMZ is discontinued for any reason.  Also, the investigator may 
continue BBI608 in combination with TMZ or BBI608 monotherapy after the 
initial demonstration of radiographic progression and in the absence of 
intolerable toxicities.  The patient will also get repeat tumor assessments after 4-
6 weeks. Treatment with BBI608 (with or without TMZ) will continue until 
unacceptable toxicity, further disease progression (clinical or radiological), or


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another discontinuation criterion is met.
Criteria for 
Determination of 
Dose-Limiting 
Toxicity: 
A DLT is defined by the occurrence of any of the following toxicities possibly, 
probably or definitely related to BBI608 or to BBI608 in combination with TMZ
during the first 28 days of combination treatment: 
xCTCAE Grade 3 thrombocytopenia with clinically significant bleeding
xCTCAE Grade 4 hematological toxicity. 
xCTCAE Grade 3 non-hematological toxicity, except:
o Grade 3 nausea, vomiting, anorexia, diarrhea or fatigue that 
persist <7 days with appropriate supportive care.
xCTCAE Grade 4 non-hematological toxicity
o Because DVT and PE are common complications among GBM 
patients, the first occurrence of DVT or PE will not be 
considered a DLT. 
xToxicities leading to delay of study treatment for ≥ 14 days
xDuring the post-surgical period and prior to initiation of combination 
therapy with BBI608 and TMZ, any grade 3 or greater hematological 
or non-hematological toxicity that cannot be attributed to the surgical
procedure or to typical post-operative complications
xAny other toxicity that in the view of the Principal Investigator represents 
a clinically significant hazard to the patient 
Whether a DLT has occurred will be assessed during the first 28 days of 
combination therapy.  DLTs will be determined from adverse events, and 
changes from baseline in physical examination findings and in laboratory 
parameters.  Patients who do not complete 28 days of combination therapy for 
reasons other than DLT may be replaced.
Adverse events considered related to TMZ only will not be considered DLTs for 
BBI608 in combination with TMZ. 
Pharmacokinetic 
and 
Pharmacodynamic 
Variables: 
Pharmacokinetic variables to be determined include maximum plasma drug 
concentration (Cmax), area under the time-concentration curve (AUC), and 
terminal half-life. Blood samples for PK determination will be drawn over 12
hours on Day 1 and again on Day 5 of Cycle 1 of BBI608 and TMZ 
combination therapy. Archival tissue (15-30 unstained slides or tissue block) 
from primary tumor resection will be collected from all patients.  When 
possible, the following tissue will be collected from the repeat resection 
procedure: fresh frozen tissue and formalin fixed, paraffin-embedded, tissue. 
Archival samples will be used to examine potential predictive biomarkers for 
therapeutic activity of BBI608 or of BBI608 plus TMZ, while samples obtained 
from the on-study resection procedure will be used to investigate evidence of 
BBI608 presence in resected tumor tissue and to evaluate pharmacodynamics. 
Statistical Methods: 
In general, categorical variables will be summarized as the number and 
percentage of patients in each category. Continuous variables will be 
summarized by the mean, standard deviation, median, minimum, and maximum.
The primary population for the efficacy endpoints will be the Per Protocol 
population defined as the population of patients who have been treated with at 
least 80% of 1 complete cycle of BBI608 and TMZ. Analyses will also be 
performed on the Intent-to-Treat (ITT) population in each arm. Analyses will 
also be performed on The primary endpoint is PFS-6, defined as the proportion 
of patients with PFS (i.e. absence of documented objective progression or death) 


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at 6 months after enrollment.
With a sample size of 30 patients, the lower bound of the two-sided 80% 
confidence interval, as estimated by the exact binomial method using a projected 
PFS-6 rate of 20%, will be greater than 10%, and provides meaningful 
information for further clinical evaluation.
The secondary endpoints will include OS (overall survival), defined as the 
interval between the date of patient enrollment until death; PFS (progression 
free survival), defined as the interval between the date of patient enrollment and 
objective progression or death; ORR (objective response rate), the proportion of 
patients with a documented complete response or partial response according to 
the RANO criteria; and DCR (disease control rate), the proportion of patients 
with documented stable disease, partial response, or complete response 
according to RANO criteria. 
Safety analyses will include adverse events, SAEs, laboratory tests, and physical 
examination changes from baseline.  All patients receiving at least one daily 
dose of BBI608 will be considered evaluable for safety analyses.  In addition to 
the evaluation and categorization of adverse events, listings of laboratory test 
results collected at baseline and during the study will be generated.  Descriptive 
statistics summarizing the changes in those laboratory tests over time will be 
presented. 


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TABLE OF CONTENTS
SYNOPSIS .................................................................................................................................2 
1 
PRECLINICAL SUMMARY AND STUDY RATIONALE ..........................................13 
1.1 
Scientific Background of BBI608 ..........................................................................13 
1.2 
Glioblastoma Multiforme (GBM) ..........................................................................13 
1.3 
Cancer Stem Cells and GBM .................................................................................14 
1.4 
Mechanism of Action .............................................................................................14 
1.5 
Preclinical Efficacy ................................................................................................14 
1.6 
GLP Toxicology.....................................................................................................15 
1.7 
Safety and Encouraging Signs of Antitumor Activity in Phase I and II Studies ...16 
2 
STUDY OBJECTIVES ....................................................................................................17 
2.1 
Primary Objectives.................................................................................................17 
2.2 
Secondary Objectives.............................................................................................17 
3 
SELECTION OF STUDY POPULATION .....................................................................18 
3.1 
Inclusion Criteria ...................................................................................................18 
3.2 
Exclusion Criteria ..................................................................................................19 
3.3 
Number of Patients ................................................................................................20 
4 
INVESTIGATIONAL PLAN ..........................................................................................21 
4.1 
Overall Study Design .............................................................................................21 
4.2 
Rationale for Study Design ....................................................................................22 
4.3 
Selection of Dose ...................................................................................................22 
4.4 
Criteria for Dose De-escalation and Determination of Dose-Limiting Toxicity ...22 
4.5 
Dose-Limiting Toxicity .........................................................................................23 
4.6 
Study Duration .......................................................................................................24 
5 
STUDY VISITS ...............................................................................................................24 
5.1 
Overview ................................................................................................................24 
5.2 
Informed Consent...................................................................................................24 
5.3 
Pre-Study Evaluations (Baseline) ..........................................................................25 
5.4 
On-Study Assessments...........................................................................................25 
5.4.1 
Pre-Surgical BBI608 Monotherapy Run-in Phase (ARM A only) ..............25 
5.4.1.1 
Run-in Week 1 (Day 1) ......................................................................26 
5.4.1.2 
Run-in Week 2 (Day 8 - Day of Surgery) ..........................................26 
5.4.2 
Surgical Resection of Recurrent GBM ........................................................26 
5.4.3 
BBI608 Combination Therapy with Temozolomide ...................................27 
5.4.3.1 
Cycle 1 (Day 1) ..................................................................................27 
5.4.3.2 
Cycle 1, Day 5 ....................................................................................28 
5.4.3.3 
Cycle 1, Day 15 ..................................................................................28 
5.4.3.4 
Cycle 2 and Beyond ...........................................................................28 
5.5 
Tumor Evaluation Visits ........................................................................................29 
5.6 
End of Study Evaluation ........................................................................................29 
5.7 
Discontinuation from Study ...................................................................................30 
6 
STUDY PROCEDURES .................................................................................................31 
6.1 
Medical History .....................................................................................................31 
6.2 
Physical Examination.............................................................................................32 
6.3 
Clinical Laboratory Tests .......................................................................................32 
6.4 
Pharmacokinetic Assessments ...............................................................................32 


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6.5 
Pharmacodynamic Assessments ............................................................................33 
6.6 
Archival and On-Study Tumor Tissue Collection .................................................34 
7 
TREATMENT .................................................................................................................34 
7.1 
BBI608 ...................................................................................................................34 
7.1.1 
Investigational Product Accountability .......................................................34 
7.1.2 
BBI608 Administration ................................................................................35 
7.1.3 
Temozolomide (TMZ) Administration ........................................................35 
7.2 
Dose Modifications ................................................................................................35 
7.2.1 
BBI608 .........................................................................................................35 
7.2.2 
Temozolomide .............................................................................................37 
7.3 
Treatment Compliance ...........................................................................................39 
7.4 
Blinding..................................................................................................................40 
7.5 
Prior Treatment ......................................................................................................40 
7.6 
Concomitant Medication ........................................................................................40 
7.6.1 
Permitted Treatment ....................................................................................40 
7.6.2 
Prohibited Treatment ...................................................................................41 
8 
SAFETY ASSESSMENTS ..............................................................................................42 
8.1 
Adverse Events ......................................................................................................42 
8.1.1 
Assessments .................................................................................................42 
8.1.2 
Definitions ...................................................................................................42 
8.2 
Serious Adverse Events .........................................................................................43 
8.2.1 
Definitions ...................................................................................................43 
8.2.2 
Reporting Serious Adverse Events ..............................................................43 
9 
ASSESSMENT OF ANTI-TUMOR ACTIVITY ............................................................44 
9.1 
Method of Measurement ........................................................................................44 
9.2 
Baseline Documentation of “Target” and “Non-Target” Lesions .........................44 
9.3 
Response Criteria ...................................................................................................45 
9.4 
Evaluation of Best Overall Response ....................................................................47 
10 PLANNED STATISTICAL METHODS ........................................................................48 
10.1 
General Considerations ..........................................................................................48 
10.2 
Determination of Sample Size ...............................................................................48 
10.3 
Analysis Populations ..............................................................................................48 
10.4 
Demographics and Baseline Characteristics ..........................................................48 
10.5 
Statistical Analysis of Pharmacokinetic Variables ................................................49 
10.6 
Safety Analysis ......................................................................................................49 
11 QUALITY CONTROL AND ASSURANCE .................................................................49 
11.1 
Compliance with the Protocol ................................................................................50 
11.2 
Registration and Enrollment ..................................................................................50 
11.3 
Removal, Replacement, or Early Withdrawals of Subjects ...................................50 
12 COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL  
CONSIDERATIONS AND INFORMED CONSENT ....................................................50 
12.1 
Institutional Review Board ....................................................................................50 
12.2 
Compliance with Good Clinical Practice and Ethical Considerations ...................51 
12.3 
Informed Consent and Permission to Use Private Health Information ..................51 
13 STUDY MANAGEMENT ..............................................................................................52 
13.1 
Amendments to the Protocol ..................................................................................52 


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13.2 
Investigator Brochure and Information Materials ..................................................52 
13.3 
Pre-investigational Documents ..............................................................................52 
13.4 
Drug Inventory Record ..........................................................................................53 
13.5 
Disposition of Used and Unused Study Drug ........................................................53 
13.6 
Study Records ........................................................................................................53 
13.7 
Record Retention ...................................................................................................54 
13.8 
Subject Confidentiality ..........................................................................................54 
13.9 
Monitoring .............................................................................................................54 
13.10 Case Report Form (CRF) Completion ...................................................................54 
13.11 Final Site Report ....................................................................................................55 
13.12 Final Study Report .................................................................................................55 
13.13 Use of Information .................................................................................................55 
13.14 Publication .............................................................................................................56 
13.15 Research Outside the Terms of this Protocol .........................................................56 
APPENDIX A:  SCHEDULE OF ASSESSMENTS  (ARM A) .............................................57 
APPENDIX B:  SCHEDULE OF ASSESSMENTS  (ARM B) ..............................................59 
APPENDIX C:  PERFORMANCE STATUS .........................................................................60 
SPONSOR SIGNATURE ........................................................................................................61 
INVESTIGATOR’S SIGNATURE .........................................................................................62 
REFERENCES ........................................................................................................................63 
 


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


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


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


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1
PRECLINICAL SUMMARY AND STUDY RATIONALE  
1.1
Scientific Background of BBI608 
Recent studies have uncovered the presence of cancer stem cells (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 holds great promise for cancer patients [Boman 
and Wicha, 2008; Clevers, 2011; Lobo et al., 2007; Magee et al., 2012; Singh and Settleman, 
2010). Specifically in glioblastoma multiforme (GBM), CSCs have been reported to be 
responsible for both disease pathogenesis and resistance of GBM to therapy [Singh 2004, 
Chen 2012, Bao 2006, Beier 2008].
BBI608 is a small molecule that targets cancer by blocking self-renewal of and inducing 
apoptosis in cancer stem cells. While not a kinase inhibitor, BBI608 works by inhibiting the 
STAT3 pathway. With their proprietary target discovery technology TPIV®, scientists at 
Boston Biomedical, Inc. have discovered that STAT3 pathway activity is critical for the self-
renewal and survival of cancer stem cells in human cancer, including GBM.
1.2
Glioblastoma Multiforme (GBM) 
GBM is a significant cause of morbidity and mortality. In the United States, 3,336 new cases 
of GBM were estimated to occur in 2012, and 2,055 of these patients died from this disease 
[NCI SEER]. GBM accounts for approximately 50% of all primary brain tumors. 
Unfortunately, GBM patients have few treatment options: standard of care consists of 
maximal resection of tumor followed by chemoradiotherapy with temozolomide (TMZ), an 
oral alkylating agent, with additional TMZ chemotherapy until progression of disease, which 
is the unfortunate outcome in nearly all patients. Despite multimodality treatment, prognosis 
with standard of care treatment remains poor, as median survival is 15-17 months [Stupp 
2005; Chinot 2014].
A retrospective review of 168 recurrent-GBM patients from a single center suggested that 
retreatment at relapse may lead to increase in progression free survival (PFS) as well as in 
overall survival (OS) [Hau 2003]. Standard treatment for recurrent GBM includes 
chemotherapy, usually administered until evidence of further disease progression, and 
possible tumor debulking in select patients. A randomized Phase 3 study comparing TMZ to 
nitrosoureas in chemotherapy-naïve patients with recurrent GBM reported no statistically 
significant difference between these two treatment arms. For the TMZ arm, the study 
reported a median PFS of 5 months and a median OS of 8.5 months [Brada 2010]. A Phase 
II study of bevacizumab in patients with recurrent GBM following adjuvant first-line TMZ 
treatment resulted in an objective response rate of 28%, 6 month PFS of 43%, and a 
decreased need for steroids, but did not result in a prolonged OS [Cloughesy 2010]. Overall, 
there is a lack of standard second-line therapy recommendations. Management of patients 


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with recurrent GBM is difficult and no re-intervention has been proven to lead to meaningful 
improvement in OS. 
At this time, treatment options for patients with recurrent GBM are limited to therapy with 
TMZ or bevacizumab, possible repeat tumor debulking, consideration of non-conventional 
radiotherapy with no established guidelines thus far, investigational regimens, and best 
supportive care. Given the morbidity associated with this disease, there is an urgent need to 
identify novel therapies that improve the outcome of patients with recurrent GBM. 
1.3
Cancer Stem Cells and GBM 
CSCs or cancer cells with stemness phenotypes are a sub-population of cancer cells that have 
self-renewal capability, are highly malignant, and are considered to be fundamentally 
responsible for malignant growth, recurrence, drug-resistance, and metastasis. Moreover, 
CSCs are highly resistant to chemotherapies and current targeted agents. CSCs have been 
isolated from almost all major tumour types, including GBM. In fact, one of the pioneering 
studies on solid tumor CSCs reported that CD133 marks GBM stem cells [Singh 2004].
Targeting stem cells, therefore, holds great promise for fundamentally advancing cancer 
treatment, including that for GBM.
Accumulating evidence indicates that CSCs play a key role in both the initiation of GBM 
[Singh 2004] and in tumor recurrence (in the latter via its role in chemoradiotherapy 
resistance) [Chen 2012, Bao 2006, Beier 2008]. Cancer stem cells have been isolated from 
human GBM using cell surface markers such as Lgr5 [Nakata 2013, Mao 2013] and CD133 
[Singh 2004, Brescia 2013]. CSCs isolated from GBM patients display both tumor-initiating 
properties and resistance to chemotherapeutics. These findings suggest that the development 
of cancer stem cell inhibitors represents a novel and compelling strategy for the treatment of 
GBM.
1.4
Mechanism of Action 
STAT3 is aberrantly activated in a wide variety of human cancers, including GBM, all of the 
major carcinomas, and in some hematologic tumors. STAT3 is a key transcription factor that 
is activated in 50-80% of GBM, is associated with advanced tumor grade, is involved in 
resistance to TMZ, and is correlated with worse outcome in both animal models of human 
GBM and in human patients, regardless of MGMT status [Carro 2010, Kohsaka 2012, 
Stechishin 2013, Lo 2008]. Importantly, STAT3 is the master transcription factor underlying 
the mesenchymal subtype of human glioma [Dunn 2012; Phillips 2006; Carr 2010].
Inhibition of STAT3 in vitro potentiates TMZ efficacy in TMZ-resistant GBM cell lines and 
data suggest that STAT3 mediates MGMT expression [Kohsaka 2012]. These data 
demonstrate that both GBM pathogenesis and chemoradioresistance may be regulated by 
STAT3 and therefore establish a powerful rationale for the development of GBM cancer 
therapies based on inhibition of STAT3 activity. 
1.5
Preclinical Efficacy 


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Cancer stem cells are intrinsically resistant (more than 5 to 10  fold) to chemotherapeutic 
drugs. BBI608 has potent activity (~100 to 500 nM) against cancer stem cells in vitro and in 
vivo, and moreover spares normal hematopoietic stem cells (IC50 not reached at 30 ʛM);
these properties offer a wide therapeutic window. The dependence on STAT3 for aberrant 
activity is conserved in various non-stem cancer cells. BBI608 has demonstrated in vitro 
efficacy against a broad spectrum of human cancer cell lines derived from both solid tumors 
and hematologic malignancies (IC50 ~100 nM to 500 nM). BBI608 monotherapy has 
demonstrated potent anti-tumor activity in vivo, and in the absence of adverse effects, in 
multiple murine xenograft models of human cancer, including those of brain, liver, head and 
neck, breast, prostate, colon, gastric and pancreatic cancers. Additionally, in vivo 
spontaneous metastasis mouse models have demonstrated that BBI608 monotherapy has anti-
metastatic activity.  
When administered in mouse xenograft models, many chemotherapeutic agents increase 
pSTAT3 levels and enrich cancer stem cell abundance.  BBI608 is able to significantly 
decrease pSTAT3 levels as well as deplete stem cell abundance, and to block the induction of 
pSTAT3 and the increase in cancer stem cells by chemotherapeutic agents. In vitro, treatment 
of GBM cell lines with BBI608 in combination with TMZ results in potent and synergistic 
spherogenesis inhibition. Additionally, combined treatment with BBI608 and TMZ
suppresses levels of p-STAT3 and E-catenin, while monotherapy with TMZ leads to up-
regulation of these proteins. These data suggest broad therapeutic potential of BBI608 in 
human GBM. 
1.6
GLP Toxicology  
GLP 28-day repeat dose toxicology studies were performed in both rats and dogs at doses of 
10, 30, and 100 mg/kg/day of BBI608 by oral gavage.   
In the rat study, 100 mg/kg was not tolerated by the male rats. Toxic observations include 
significant weight loss, soft feces and diarrhea, and decreased food consumption, which led 
to early sacrifice. These symptoms recovered in the remaining male rats within 14 days after     
termination of dosing. Female rats receiving 100 mg/kg/day showed weight loss during the 
first week of dosing; however, weight recovered during the continued dosing phase without 
significant abnormal clinical observations.  
In the rat study, abnormal laboratory findings (azotemia, hyponatremia, hypochloremia, 
hyperkalemia, polycythemia, neutrophilia, monocytosis, and lymphopenia) were observed 
primarily in moribund male rats dosed at 100 mg/kg. These findings are consistent with acute 
renal failure in the setting of dehydration and diarrhea. In rats dosed at 100 mg/kg for 28 
days, there was a mild decrease in sodium, chloride, and albumin levels and mild elevation of 
white blood cells, red blood cells, neutrophils, lymphocytes and monocytes. No significant 
abnormal laboratory findings were seen in recovered rats, suggesting that these abnormal 
laboratory findings are reversible. There were no abnormal laboratory findings in rats dosed 
at 10 and 30 mg/kg.  
In the rat study, histopathological findings were noted in the rats dosed at 100 mg/kg, 
primarily in moribund male rats, including microscopic changes in the stomach and urinary 
bladder (focal or multifocal chronic ulceration, epithelial hyperplasia, chronic active 


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inflammation or hemorrhagic changes), in lymphoid tissues (mild to marked lymphoid 
atrophy with mild to moderate lymphocyte apoptosis in thymus, mild to moderate lymphoid 
atrophy and mild to moderate mastocytosis in mesenteric lymph nodes, mild to moderate 
lymphoid atrophy in two moribund male rats dosed at 100 mg/kg, and some elevation of 
hemosiderosis in the spleen) and in adrenal glands (mild cortical vacuolation). These findings 
were considered to be non-specific changes related to the test vehicle in the setting of 
dehydration and diarrhea. There were no significant histopathological findings in recovered 
rats, suggesting that these histopathological changes are reversible. There was no significant 
test vehicle related microscopic changes in rats dosed at 30 mg/kg and at 10 mg/kg.  
In the rat study, toxicokinetics showed that all dose groups in rats achieved BBI608 exposure 
at a level well above the predicted exposure levels needed for efficacy, and exposure lasted 
beyond 10 hours.  
In the dog study, toxicity was observed in dogs receiving 100 mg/kg/day.  Toxic symptoms 
consisted of mild weight loss, emesis, diarrhea, and mucoid and soft feces. These adverse 
effects were reversible within 14 days in the setting of continued dosing. No treatment-
related clinical pathological, gross pathological, or histopathological effects were observed at 
any dose level. All dose groups achieved plasma levels of BBI608 above the predicted levels 
needed for efficacy, and exposure lasted beyond 10 hours.  
The no observable adverse effect level (NOAEL, based on clinical observation, laboratory 
tests, gross and histopathological changes) for rats administered BBI608 daily orally over 28 
days was 30 mg/kg/day (human equivalent dose: 180 mg/m2) and the NOAEL in dogs 
administered BBI608 daily orally over 28 days was 30 mg/kg/day (human equivalent dose: 
600 mg/m2). 
1.7
Safety and Encouraging Signs of Antitumor Activity in Phase I and II Studies 
In the Phase I dose escalation study of BBI608 monotherapy, 14 cohorts (N=41) were dosed 
from 20 mg to 2000 mg/day.  All of the patients in this study were in the last line of 
treatment setting. Eighteen (44%) of the patients had CRC, which was the most common type 
of cancer studied in this trial. Other types of cancers varied from 2-7% of the total, and 
included gastric/GEJ, pancreatic, NSCLC, prostate, head and neck, melanoma and others.  
The vast majority of the patients (78%) in this study had progressed on >3 prior regimens. 
Adverse events were generally mild, including grade 1-2 diarrhea, nausea, anorexia and 
fatigue with a total of 4 grade 3 events (diarrhea and fatigue). MTD was not reached. At 400 
mg/day, the plasma concentration of BBI608 was sustained at a concentration > 1.5 uM 
(several fold above the IC50 [avg.~0.09 uM]) for >8 hours.  RP2D has been determined to be 
480 mg bid. Among those evaluable for tumor response (using RECIST 1.1 criteria), disease 
control (disease stabilization and regression) was observed in 65% of patients. Prolonged 
time to progression was observed in 46% of evaluable patients, including patients with CRC, 
head & neck, gastric, ovarian, melanoma, and breast cancers. In the subset of patients with 
CRC (N=18), disease control was seen in 67% of those evaluable.  Median progression free 
survival (PFS) and overall survival (OS) of 14 and 47 weeks, respectively, were observed in 
evaluable CRC patients.  Median OS for biomarker-positive (nuclear E-catenin and high p-
STAT3) CRC patients was 53 weeks and 54 weeks, respectively.  In this study, BBI608 has 
shown a favorable safety and PK profile, and encouraging signs of activity, particularly in 
CRC.  


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In addition, BBI608 has been evaluated in combination therapy in the Phase Ib/II studies. 
BBI608 has been safely combined at full dose with paclitaxel or capecitabine (BBI608-201 
and BBI608-224, respectively), with a similar adverse event profile compared to that of 
either BBI608 or paclitaxel monotherapy. The RP2D of BBI608 in combination with weekly 
paclitaxel or capecitabine has been determined to be 480 mg twice daily.  
In a previously conducted subcohort of BBI608-201 with Budesonide prophylaxis for GI 
symptoms, budesonide an oral topical corticosteroid led to marked decrease in the incidence 
and severity of gastrointestinal symptoms.  Budesonide decreased the incidence and severity 
of diarrhea, abdominal pain, nausea, vomiting and fatigue in patients who received oral 
Budesonide 9mg po QD when combined with BBI608 at 480mg either as monotherapy or 
combined with weekly Paclitaxel and at 240mg either as monotherapy or combined with 
weekly Paclitaxel.  Plasma levels of BBI608 in subjects taking budesonide were similar to 
the ones that had not received budesonide prophylaxis at BBI608 doses of 240mg and 480mg 
bid, either with or without the addition of weekly Paclitaxel infusion. 
Given the clinical data thus far, and the encouraging in vitro and in vivo results seen with the 
combination of BBI608 with TMZ, further evaluation of BBI608 in combination therapy to 
treat GBM is warranted.  
2
STUDY OBJECTIVES 
2.1
Primary Objectives 
The primary objective of this study for the Phase Ib component is: 
x
To determine the safety, tolerability of BBI608 when administered in combination 
with temozolomide (TMZ). 
The primary endpoint of this study for the Phase II component is: 
x
To determine progression-free survival at 6-months (PFS-6). 
2.2
Secondary Objectives 
The secondary objectives for the Phase Ib component of this study are: 
x
To assess preliminary anti-cancer activity of BBI608 when administered in 
combination with TMZ. 
x
To determine the pharmacokinetic profile of BBI608 when administered in 
combination with TMZ. 
x
To determine the pharmacodynamics (i.e., identify biomarkers) of BBI608 when 
administered as monotherapy prior to repeat surgical resection and when administered 
in combination with TMZ.  
The secondary endpoints of this study for the Phase II component are: 
x
To assess the median progression free survival (PFS).


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x
To assess the median overall survival (OS).  
x
To assess the disease control rate (DCR). 
x
To assess the objective response rate (ORR), when applicable. 
3
SELECTION OF STUDY POPULATION  
This study will be conducted in patients with histologically confirmed GBM at first 
recurrence of disease following front-line therapy that includes maximal resection, 
radiotherapy, and chemotherapy with TMZ (the latter is allowed but not mandatory for 
enrollment), and for whom treatment with TMZ is an appropriate treatment option in the 
judgment of physician investigators and who may or may not be eligible for repeat surgical 
resection.  Patients who are eligible for further surgical resection will be enrolled into Arm 
A.  Patients who are not eligible for further resection will be enrolled into Arm B.  
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. A histologically confirmed supratentorial GBM at first recurrence/progression 
following standard front-line therapy, for which treatment with TMZ would be 
acceptable as determined by the Investigator.  
a.
Recurrence is defined as progression following initial therapy (i.e. radiation+/- 
chemo, if that was used as initial therapy). The intent therefore is that the 
patient has had no more than 1 prior treatment regimen.  
3. Previously received standard front-line GBM treatment including maximal surgical 
resection followed by external beam radiation therapy.  
a.
Prior concurrent chemoradiation with TMZ is allowed but not mandatory. A 
minimum of 12 weeks following the last dose of Radiotherapy or TMZ-
Radiotherapy must occur prior to the first documented progression.  After that 
period in patients receiving adjuvant TMZ a wash out period of 4 weeks 
before first dose of BBI608 is required. 
4. Patients may or may not be candidates for repeat surgical resection of the 
recurrent/progressed GBM. 
5. Patients must have unequivocal evidence of tumor recurrence/progression by MRI at 
a minimum of 12 weeks following completion of chemoradiation or radiation therapy. 
6. Baseline scan performed within 28 days of enrollment.
7. Patients on concurrent corticosteroid treatment are eligible for enrollment as long as 
they are on a stable or decreasing dose of corticosteroids (or no corticosteroids) and 
neurologically stable from the time of their baseline scan and/or at least 5 days before 
starting treatment with BBI608. During this period the maximum total daily dose of 
dexamethasone should not exceed 8 mg administered orally (or bioequivalent). 


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8. Patients must have measurable or non-measurable disease by RANO criteria.
9. Patients treated with CYP1A2 enzyme inducing anti-epileptics (including 
phenobarbital, phenytoin, and carbamazepine) must be switched to an alternative anti-
epileptic agent at least 14 days prior to first dose of BBI608. 
10. ≥18 years of age.  
11. ECOG (Eastern Oncology Cooperative Group) performance status of 0 or 1
(corresponding to a Karnofsky performance status score ≥70%) (Appendix C).
12. Male or female patients of child-producing potential agree to use contraception or to 
avoid contributing to a pregnancy or becoming pregnant, respectively, during the
study and for 30 days after the last BBI608 dose. 
13. Females of childbearing potential have a negative serum pregnancy test. 
14. Aspartate transaminase (AST) and alanine transaminase (ALT) levels <3.0 x upper 
limit of normal (ULN). 
15. Hemoglobin (Hgb) ≥9 g/dl.
16. Total bilirubin level d1.5 × ULN. 
17. Creatinine level d1.5 u ULN or creatinine clearance >60 mL/min/1.73 m2 for patients 
with creatinine levels above institutional normal (as determined by Cockroft-Gault 
equation). 
18. Absolute neutrophil count t1.5 x 109/L. 
19. Platelets ≥100 x 109/L. 
20. Life expectancy estimated at ≥3 months.
21. Patients have recovered from toxicities (to Grade ≤ 1) related to their previous 
therapy. 
3.2
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
1. TMZ-Radiotherapy administration or radiotherapy within 12 weeks of the first 
documented 
progression. 
 
Other 
chemotherapy 
including 
Temozolomide 
monotherapy, immunotherapy or investigational agents must be stopped a minimum 
of 4 weeks prior to the first dose of BBI608.  
2. Previous treatment with bevacizumab or other anti-VEGF agents 
3. Any prior anti-cancer treatment for disease recurrence/progression. 
4. More than one instance of disease recurrence/progression.
5. Presence of diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial 
disease. 
6. Major surgery within 4 weeks prior to enrollment. 


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a.
Patients who had repeat surgical resection to treat GBM are allowed to start 
the Arm B portion of this study after 15 days of the surgery. 
7. Pregnant or breastfeeding.  
8. Treatment with EIAEDs within 14 days of first dose of BBI608. 
9. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal 
Investigator, prevent absorption of an orally available agent (e.g., Crohn’s disease, 
ulcerative colitis, extensive gastric resection and small intestinal resection).  
10. Unable or unwilling to swallow BBI608 capsules daily. 
11. Prior treatment with BBI608.
12. Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, clinically significant non-healing or healing wounds, symptomatic 
congestive heart failure within the past 12 months, unstable angina pectoris, cardiac 
arrhythmia, significant pulmonary disease (shortness of breath at rest or mild 
exertion), uncontrolled infection, HIV, chronic hepatitis B, chronic hepatitis C, 
immunosuppressive disease, concurrent neurodegenerative disease, chronic renal 
disease/failure, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
13. Known hypersensitivity to TMZ. 
14. History of intolerance to TMZ with need to discontinue TMZ or decrease dose to < 
150 mg/m2 for days 1 through 5 of each 28 day cycle. 
3.3
Number of Patients 
The exact number of patients estimated for this trial is dependent on the number of patient 
cohorts investigated based on the toxicity encountered.  It is expected that approximately 30 
patients (including those enrolled to the DLT evaluation cohorts) will be enrolled in each arm 
of this study.  


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4
INVESTIGATIONAL PLAN 
4.1
Overall Study Design 
This is an open-label, multi-center Phase Ib/II, study of BBI608 administered in combination 
with TMZ to patients with recurrent or progressive GBM who have not received prior 
bevacizumab therapy. The study is designed to explore the safety, tolerability and 
pharmacokinetics of BBI608, and the preliminary anti-cancer activity of BBI608 in 
combination with TMZ, in adults with recurrent or progressive GBM who have not received 
prior treatment with bevacizumab and who may or may not be eligible for further surgical 
resection. The primary efficacy endpoint will be PFS-6. Secondary efficacy endpoints will 
include median PFS, OS, DCR and ORR.  
Arm A will include patients who are candidates for repeat surgical resection. These patients 
will receive 7 (±2) days of BBI608 monotherapy at a dose level of 480 mg twice daily (960 
mg total daily dose – Initial Dose) prior to resection. Following surgical clinical recovery, 
and on a date between 15-28 days following the date of surgery, BBI608 (480 mg twice 
daily) will be restarted in combination with TMZ (150 mg/m2 on days 1 through 5 of each 
28-day cycle). If a patient does not recover from surgical resection sufficiently within 28 
days to resume oral therapy with BBI608 plus TMZ, the patient should be withdrawn from 
study. Combination therapy will continue until disease progression or another 
discontinuation criterion is met.  The dose of TMZ can be increased to 200 mg/m2 for those 
patients who complete at least one cycle at 150 mg/m2 in combination with BBI608.   
Arm B will include patients who are either not candidates for repeat surgical resection or 
have undergone repeat surgical resection prior to enter the study. These patients will receive 
BBI608 (480 mg twice daily) in combination with TMZ (150 mg/m2 administered for days 1 
through 5 of each 28 day cycle) and continue treatment until disease progression or another 
discontinuation criterion is met. The dose of TMZ can be increased to 200 mg/m2 for those 
patients who complete at least one cycle at 150 mg/m2 in combination with BBI608.   
Initially, 6 patients will be enrolled into a safety cohort for each study arm. The 6-patient 
safety cohort will be evaluated for the occurrence of DLTs during the first 28 days of 
combination treatment. For patient in Arm A during the run-in period with BBI608 
monotherapy, the same DLT rules as for the combination therapy will apply.  Enrollment will 
be held if ≥ 2 patients are unable to undergo resection due to DLTs.  Enrollment will also be 
held if ≥ 2 patients have an unexpected surgical complication.
For a given arm, if > 2 out of 6 patients experience a DLT, then the BBI608 dose will be 
reduced for all patients in that arm to the next lower dose level of 240mg twice daily. 
Furthermore, an additional 6-patient safety cohort in that study arm will be enrolled at the
reduced dose-level and evaluated for DLT as described below.  
Recommended Phase 2 Dose (RP2D) will be defined as the dose-level evaluated at which < 1
of 6 patients per cohort experiences a DLT.  
An additional 24 patients may be enrolled at RP2D in each arm. 
For both study arms, cycle length will be 28 days. Combination-therapy cycles will consist of 
BBI608 administration daily for 28 days and TMZ administration on days 1-5 of each cycle.   


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Tumor assessments using RANO criteria will be performed every eight weeks from the 
initiation of combination therapy with BBI608 and TMZ, or otherwise as clinically indicated. 
Number of Subjects with 
DLT at a Given Dose Level
for a Given Study Arm
Dose De-escalation Decision Rule
<1 out of 6
This dose
level will be considered RP2D for the 
combination regimen (BBI608+TMZ)
>2 out of 6
Initial dose level will be reduced to a dose chosen by the 
Investigator and BBI medical monitor.  Six (6) additional 
subjects will be entered at this lower dose level and
evaluated for DLT over the first 28 days of combination 
therapy.
4.2
Rationale for Study Design  
Considerable data has been collected from the Phase I monotherapy study of BBI608 as well 
as from phase 1b/II studies conducted in advanced oncology patients who have failed 
multiple previous regimens. BBI608 has shown a favorable safety and PK profile and 
encouraging signs of activity. Combination of cancer stem cell therapeutics with 
chemotherapy would allow simultaneous inhibition of cancer stem cells as well as non-stem 
tumor bulk cells. Given the clinical data thus far, and the encouraging in vitro and in vivo
results seen with combination of BBI608 with TMZ, further evaluation of BBI608 in 
combination therapy to treat GBM is warranted. 
4.3
Selection of Dose 
Dose escalation for BBI608 has been successfully conducted from 20 to 2000 mg total daily 
dose. MTD was not reached and RP2D was determined based on pharmacokinetics. Adverse 
events observed in the BBl608 monotherapy phase I trial have been generally mild (Grade 1-
2) with the most common being diarrhea, nausea, anorexia and fatigue.  Grade 3 events 
include fatigue and diarrhea. No bone marrow suppression or neuropathy was observed. 
In phase 1b/II studies, BBI608 has been successfully combined at full dose (480 mg twice 
daily) with weekly paclitaxel or capecitabine, without any signs of adverse effects that differ 
from those that occur when either agent is administered as monotherapy.  
Dosing of BBI608 in each combination arm of this trial will be initiated at 480 mg twice 
daily; this dose is the monotherapy RP2D for BBI608 and is also the RP2D of BBI608 in 
combination with weekly paclitaxel or capecitabine.
4.4
Criteria for Dose Escalation and Determination of Dose-Limiting Toxicity 


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Dose-Limiting Toxicity (DLT) will be evaluated separately in each study arm. Patients 
evaluable for DLT assessment are defined as having been exposed to at least 28 days of 
continuous daily administration of BBI608 in combination with TMZ (i.e. DLT evaluation 
period starts from the first administration of TMZ), or having had a protocol-defined DLT at 
any time within this period. Based on the tolerability and safety of evaluable patients, 
enrollment of additional patients will occur according to criteria described below:  
x
If <1 treated patients experience a BBI608-related DLT (defined below) by Day 28 of 
Cycle 1 of combination therapy with TMZ, then additional patients will be enrolled at 
this BBI608 dose into the RP2D expansion cohort.
x
If >2 treated patients at a dose level experience a BBI608-related DLT by Day 28 of 
Cycle 1, patient enrollment into this BBI608 dose level cohort will stop and the 
BBI608 dose will be reduced to the next lower  dose level of 240mg twice daily. An
additional 6-patient safety cohort will be enrolled at the reduced dose-level and 
evaluated for DLT.  
x
RP2D of BBI608 with TMZ will be defined as the dose level at which no more than 
one patient with DLT is observed among six patients.
The BBI medical Monitor and Principal Investigator will review all significant BBI608-
related toxicities to determine whether the initial BBI608 dose (480 mg twice daily) requires 
adjustment.  Lower BBI608 doses may be assigned after agreement between the BBI Medical 
Monitor and the Principal Investigator.  
4.5
Dose-Limiting Toxicity 
A DLT is defined by the occurrence of any of the following toxicities possibly, probably or 
definitely related to BBI608 or BBI608 in combination with TMZ during the first 28 days of 
combination treatment: 
x CTCAE Grade 3 thrombocytopenia with clinically significant bleeding 
xCTCAE Grade 4 hematological toxicity.  
xCTCAE Grade 3 non-hematological toxicity, except: 
o Grade 3 nausea, vomiting, anorexia, diarrhea or fatigue that persist <7 days 
with appropriate supportive care. 
xCTCAE Grade 4 non-hematological toxicity
o Because DVT and PE are common complications among GBM patients, the 
first occurrence of DVT or PE will not be considered a DLT.  
xToxicities leading to delay of study treatment for ≥ 14 days
xDuring the post-surgical period and prior to initiation of combination therapy with 
BBI608 and TMZ, any grade 3 or greater hematological or non-hematological 
toxicity that cannot be attributed to the surgical procedure or to typical post-operative 
complications 
xAny other toxicity that in the view of the Principal Investigator represents a clinically 
significant hazard to the patient  


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Whether a DLT has occurred will be assessed during the 28 days of the first cycle of 
combination treatment with TMZ and during the run in and post-operative period of Arm A.  
DLT will be determined from adverse events and changes from baseline in physical 
examination findings and in laboratory parameters. 
To be considered evaluable for DLT, compliance with the assigned dose of BBI608 and 
TMZ must be ≥ 80%.  Patients who do not complete 28 days of combination therapy for 
reasons other than DLT or patients who are not eligible for DLT assessment may be replaced.  
Adverse events considered related to TMZ only will not be considered DLTs for BBI608 in 
combination with TMZ.   
4.6
Study Duration  
Patients will receive treatment with BBI608 until progression of disease (clinical or 
radiological), unacceptable toxicity, or another discontinuation criterion is documented (see 
Section 5.7).   
5
STUDY VISITS 
5.1
Overview 
Study Visits will consist of a Pre-Study Evaluation, during which the patient is evaluated to 
determine suitability for entry into the study; On-Treatment Evaluations, during which the 
patient is regularly evaluated during the conduct of the study; and an End-of-Study 
Evaluation (See APPENDIX A and APPENDIX B for schedules of Assessments). 
Following the Pre-Study Evaluation and a determination by a Principal Investigator that the 
patient meets all inclusion/exclusion criteria, and after the patient signs the informed consent, 
the patient will be considered enrolled in the study.   
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.   
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.   


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Informed consent may be obtained within approximately one month prior to the first dose of 
BBI608.  All screening procedures (with exception of baseline MRI which should be 
performed within 28 days prior to enrollment) should be performed within 10 days of the 
first dose of BBI608 (unless otherwise noted).   
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 following will be evaluated and documented within 10 days prior to first dose of 
BBI608: 
x
Medical history 
x
Physical examination including a neurologic exam 
x
ECOG performance status score (see APPENDIX C) 
x
Vital signs (weight, temperature, blood pressure, height, respiration and pulse) 
x
Adverse Event assessment (from the date of informed consent) 
x
Assessment of concomitant medications from 28 days prior to the start of study 
treatment 
x
Hematology (see Section 6.3) 
x
Biochemistry (see Section 6.3) 
x
Urinalysis (see Section 6.3)
x
Serum pregnancy test (if applicable) 
x
Archival tissue will be obtained as described in the Laboratory Manual once the 
patient has been enrolled. 
x
12-lead electrocardiogram (ECG) 
x
Tumor measurement [magnetic resonance imaging (MRI) scan]*
* MRI scan performed within 28 days of the first scheduled dose of BBI608 can be used for 
baseline assessment if it was performed while off steroids or on a stable or decreasing steroid 
dosage for at least 5 days; otherwise, MRI should be performed within 14 days of dosing.  
This will be the baseline scan for patients in ARM B; repeat MRI obtained within 48-72 
hours following surgery will be the baseline scan for the patients in ARM A for purposes of 
response assessment.
5.4
On-Study Assessments  
5.4.1
Pre-Surgical BBI608 Monotherapy Run-in Phase (ARM A only) 
These assessments will be performed ONLY for patients enrolled into Arm A of the study. 
Patients enrolled into Arm B of the study will start the study with the initiation of 
combination therapy with BBI608 and TMZ (section 5.4.3). 


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5.4.1.1 Run-in Week 1 (Day 1) 
A Run-in Week 1, Day 1 visit should ONLY occur during the Pre-Surgical BBI608 
Monotherapy Phase of the study and ONLY for patients enrolled into Arm A. Patients who 
meet all inclusion and exclusion criteria will have the following assessments: 
x
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
x
Record concomitant medication  
x
Assess adverse events (AE) 
x
Dispense BBI608 (7 (±2) day supply plus 2 extra days), please see the Pharmacy 
Manual for further information.
5.4.1.2 Run-in Week 2 (Day 8 - Day of Surgery) 
A Run-in Day 8 visit should ONLY occur during the Pre-Surgical BBI608 Monotherapy 
Phase of the study and ONLY for patients enrolled into Arm A. Patients will have the 
following assessments:  
x
ECOG performance status score 
x
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
x
Hematology (see Section 6.3) 
x
Biochemistry (see Section 6.3) 
x
Urinalysis (see Section 6.3)  
x
Assess adverse events (AE) 
x
Record concomitant medication including any changes in doses of corticosteroids  
5.4.2
Surgical Resection of Recurrent GBM 
ONLY patients enrolled into Arm A will undergo surgical resection of GBM. 
BBI608 will be administered for 7 (±2) days prior to a planned surgical resection of recurrent 
GBM.  BBI608 will be administered on the morning of the surgical procedure (Run-in Week 
2 Day 8) and BBI608 will remain held pending clinical post-operative recovery of the patient 
as determined by the investigator, for up to 28 days after surgery.  Tumor sample will be 
obtained at time of surgical resection from T1/gadolinium enhanced lesion(s) as well as 
T2/FLAIR infiltrating tumor lesions and will be used to investigate BBI608 presence in the 
resected tumor tissue and will be used for pharmacodynamics analysis (please see the 
Laboratory Manual for additional information). Additionally, blood sample will be obtained 
at time of surgery to evaluate BBI608 pharmacokinetic (PK) exposure in the plasma (please 
see the Laboratory Manual for additional information).  The time of BBI608 administration 
on the day of surgery and the collection times of blood sample will be recorded. 
Tumor samples that are obtained at the time of surgical resection and are labeled with study 
protocol identification number and patient identification number will be sent to a regulatory 
authority-approved tumor bank affiliated with the study site, or to the study site pathology 
department if the site does not have a regulatory authority-approved tumor bank. In the event 


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that there is difficulty with establishment of histological diagnosis, tumor tissue will be made 
available to the pathology department at all study sites. Processing of all tumor tissue will 
include creation of both fresh frozen samples for PK analysis as well as blocks of formalin 
fixed paraffin-embedded (FFPE) samples for PD analysis. 
An MRI will be performed 48-72 hours following surgery and will be used as the baseline 
scan for the purposes of tumor response evaluation in the patients who undergo surgical 
resection. 
5.4.3
BBI608 Combination Therapy with Temozolomide  
Following clinical post-operative recovery, Arm A patients will resume the study with this 
combination treatment phase. Patients enrolled into Arm B will begin the study directly at 
this phase. 
5.4.3.1 Cycle 1 (Day 1) 
Patients will have the following assessments: 
x
ECOG performance status score^ 
x
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
x
Physical examination including a neurologic exam^ 
x
Serum pregnancy test (if applicable)- Arm A only 
x
12-lead electrocardiogram (ECG)* 
x
Hematology (see Section 6.3)^ 
x
Biochemistry (see Section 6.3)^ 
x
Urinalysis (see Section 6.3)^ 
x
Assess adverse events (AE) 
x
Record concomitant medication including any changes in doses of corticosteroids 
x
Dispense BBI608 (28 day supply plus 3 extra days), please see the Pharmacy Manual 
for further information 
x
Dispense TMZ ** 
x
Blood samples for pharmacokinetics, red blood cell pellet Cycle 1 ONLY (please see 
the Laboratory Manual for further information)*** 
^ For patients in Arm A only.  
* The 12-lead electrocardiogram on Cycle 1 Day 1 should be obtained two hours after TMZ 
has been administered. 
** A 3 hour interval between the first daily dose of BBI608 and the administration of TMZ is 
required on Days 1 and 5 of Cycle 1 only, in order to standardize PK interpretation. On all 
other days, the first daily administration of BBI608 can precede the administration of TMZ 
by 0-4 hours. 
***Pharmacokinetics to be collected in Phase Ib/DLT assessment cohorts only 


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5.4.3.2 Cycle 1, Day 5 
The patient will have the following assessments: 
x
ECOG performance status score 
x
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
x
Assess adverse events (AE) 
x
Record concomitant medication including any changes in doses of corticosteroids 
x
Blood samples for pharmacokinetics, red blood cell pellet Cycle 1 ONLY (please see 
the Laboratory Manual for further information)***
** A 3 hour interval between the first daily dose of BBI608 and the administration of 
TMZ is required on Days 1 and 5 of Cycle 1 only, in order to standardize PK 
interpretation. On all other days, the first daily administration of BBI608 can precede the 
administration of TMZ by 0-4 hours. 
***Pharmacokinetics to be collected in Phase Ib/DLT assessment cohorts only 
5.4.3.3 Cycle 1 and Cycle 2 Day 8 (during Phase Ib) 
The patient will have the following assessments:  
xHematology (see Section 6.3) 
xBiochemistry (see Section 6.3) 
xUrinalysis (see Section 6.3) 
5.4.3.4 Cycle 1 and Cycle 2, Day 15 
The patient will have the following assessments:  
x
ECOG performance status score 
x
Vital signs (weight, temperature, blood pressure, respiration and pulse)  
x
Hematology (see Section 6.3) 
x
Biochemistry (see Section 6.3) 
x
Urinalysis (see Section 6.3) 
x
Assess adverse events (AE) 
x
Record concomitant medication including any changes in doses of corticosteroids 
5.4.3.5 Cycle 1 and Cycle 2 Day 22 (during Phase Ib) 
The patient will have the following assessments: 
xHematology (see Section 6.3) 
xBiochemistry (see Section 6.3) 
xUrinalysis (see Section 6.3) 
5.4.3.6 Cycle 2 and Beyond 
Day 1 
x
Physical examination including a neurologic examination 
x
ECOG performance status score 


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x
Vital signs (weight, temperature, blood pressure, respiration and pulse) 
x
Serum pregnancy test (if applicable) 
x
Hematology (see Section 6.3) 
x
Biochemistry (see Section 6.3) 
x
Urinalysis (see Section 6.3) 
x
Assess adverse events (AE) 
x
Record concomitant medication including any changes in doses of corticosteroids 
x
Dispense BBI608 (28 day supply plus 3 days), please see the Pharmacy Manual for 
further information 
x
Dispense TMZ  
5.5
Tumor Evaluation Visits 
For patients in Arm A, an MRI will be performed within 48-72 hours of surgery and will be 
used as the baseline exam for the purposes of tumor response evaluation in the patients who 
undergo surgical resection. 
In both study arms, disease status and tumor response will be assessed at eight-week intervals 
until objective disease progression, or as clinically indicated, beginning approximately 8 
weeks following initiation of combination therapy with BBI608 and TMZ.  Standard imaging 
studies will be performed according to institutional procedures.  Tumor response will be 
evaluated using the guidelines for Response Assessment in Neuro-Oncology (RANO)
Working Group criteria outlined in Section 9, and study Case Report Forms (CRFs) will 
include relevant lesion measurements as determined by the study site. De-identified 
radiologic image dictation report as well as de-identified copies of the radiologic images for 
independent review may be requested in cases where radiologic assessment is in question.    
Once clinical or radiological progression of disease during BBI608 therapy is documented, 
patients may continue treatment with BBI608 at the discretion of their treating physician. 
5.6
End of Study Evaluation 
All patients will be followed 14-30 days after the last dose of BBI608.  If a patient is 
removed from the study due to drug-related adverse events, the patient will be followed to 
evaluate any drug-related AEs that occurred either during the study or within 30 days of the 
last BBI608 dose.  The patient will be followed until resolution of the AE or for 30 days, 
whichever is longer.  In the presence of toxic effects, follow-up visits will be required every 
four weeks until all study related toxicities have resolved to baseline (or < CTCAE Grade 1), 
have stabilized, or are deemed irreversible.   
The following assessments will be made during the End of Study visit: 
x
Physical examination including a neurological examination  
x
ECOG performance status score 
x
Vital signs  (weight, temperature, blood pressure, respiration and pulse) 


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x
Serum pregnancy test (if applicable) 
x
Hematology (see Section 6.3) 
x
Biochemistry (see Section 6.3) 
x
Urinalysis (see Section 6.3) 
x
12-lead ECG 
x
Tumor marker, if applicable 
x
Tumor measurement and staging if applicable 
x
Assess adverse events 
x
Record concomitant medications including any changes in doses of corticosteroids 
After BBI608 administration is discontinued and after the EOS study visit has been 
completed, patients will be followed for important information and the occurrence of 
specified clinical endpoints: PFS and OS.  There are no further visits required specifically for 
this study once the EOS visit has taken place.   
The clinical parameters and endpoints for follow-up are specified below.  The intent is that 
the follow-up and collection of this information is 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.   
Clinical Parameters for Post-Protocol Therapy Follow-Up
Endpoint
Description
Follow-Up Frequency
Subsequent 
Therapy
Names and dates of anti-cancer 
treatment administered after 
BBI608 discontinuation.  
“Clinical Trial” can also be used if 
agent name is not publically 
available
Evidence for clinical 
endpoints will be assessed 
monthly for the first 3 
months after discontinuing 
BBI608
Then,
Every 3 months up to 1 year 
after discontinuing BBI608
Then,
Every 6 months 
thereafter**
Objective 
Disease 
Progression
Date criteria for RANO 
categorization of “PD” are met (if 
not already met during on-study 
or EOS objective assessments)*
Survival
Date of death due to any cause
*Passive follow-up only of radiologic imaging obtained subsequent to all on-study MRI 
scans and clinic visit notes detailing neurologic state and change in corticosteroid use.  
**Alternative schedules of post-protocol therapy follow-up by study site may be 
discussed with the Sponsor. 
5.7
Discontinuation from Study 
Patients will be removed from the study at any time if they meet any of the following criteria: 
x
Documented radiologic or clinical progression of disease 


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x
Noncompliance with any part of the study, as evaluated by the Principal Investigator 
and Medical Monitor 
x
Withdrawal of consent 
x
Investigator decision 
x
Lost to Follow-up 
x
Death  
x
Clinically unacceptable toxicities despite optimal treatment or dose reduction 
x
Pregnancy 
*RANO criteria serve to categorize clinical radiologic images.  Given a unique mechanism of 
action targeting cancer stem cells, BBI608 therapy may be continued in a patient who is 
clinically well, but who meets criteria for “Progressed Disease” per RANO criteria.  
Continuation of BBI608 protocol therapy in this context is allowed provided no further 
standard, approved treatment options exist; and provided the investigator assess that the 
potential benefit to the patient outweighs the potential risk and in the absence of intolerable 
toxicities, performance status decline, worsening of disease related symptoms, radiological 
findings that would warrant acute intervention and no ongoing severe toxicities that may be 
related to BBI608.  The patient will also get repeat tumor assessments after 4-6 weeks.  
Treatment with BBI608 (with or without TMZ) will continue until unacceptable toxicity, 
further disease progression (clinical or radiological), or another discontinuation criterion is 
met.
5.7.1
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 BBI608 is taken.  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 30 days after the Date of Last Dose.
6
STUDY PROCEDURES 
6.1
Medical History 
Medical history will include, but is not limited to, the following: 
x
Demography: date of birth, sex, ethnic origin, height, weight, smoking history 
x
Clinically significant prior diagnoses, surgeries, and current medications 
x
Prior cancer history, current cancer diagnosis, tumor stage at time of diagnosis, 
previous surgical therapy, previous chemotherapy, including dates and duration of 


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treatment, previous radiation therapy, including anatomic site, dose and date of 
treatment, O-6-methylguanine-DNA methyltransferase (MGMT) methylation status  
Prior records, radiology reports, radiology imaging, or procedure notes may be required in 
order to verify components of study patient history. 
6.2
Physical Examination 
Complete physical examination including height, weight, blood pressure, heart rate, 
respiratory rate, temperature (oral, axillary or tympanic) and ECOG performance status 
score. 
6.3
Clinical Laboratory Tests 
Safety laboratory determinations will include hematology, blood chemistry, and urinalyses.  
All laboratory tests required during the study must be obtained at a primary laboratory 
designated by the Principal Investigator.   
x
Hematology: CBC including hemoglobin, white blood cell count with 5-part 
differential, platelets 
x
Biochemistry:
electrolytes (sodium, potassium, and chloride), CO2, calcium, 
phosphorus, magnesium, total protein, albumin, glucose, and serum creatinine, blood 
urea nitrogen (BUN), AST, ALT, lactate dehydrogenase (LDH), alkaline 
phosphatase, total and direct bilirubin, and uric acid 
x
Routine urinalysis: dipstick including protein, specific gravity, glucose and blood 
x
Serum pregnancy test for female patients of childbearing potential 
MGMT methylation status: MGMT promoter methylation status will be assessed on archival 
tumor tissue submitted at enrollment, as well as tumor tissue obtained during the course of 
the study (i.e. specimen from surgical resection)  
6.4
Pharmacokinetic Assessments  
Patients enrolled into Arm A of the study will have blood and tumor tissue samples obtained 
at the time of surgical resection to evaluate the levels of BBI608 in plasma and tumor tissue. 
A single blood sample will be obtained as close to the time of tumor resection as possible. 
The time of BBI608 administration on the day of surgery and the collection times of blood 
sample will be recorded. Details on the collection, storage and shipping of these samples are 
described in the Laboratory Manual. 
Additionally, blood samples will be collected from all patients in the Phase Ib/DLT 
assessment cohorts to assess the pharmacokinetics (PK) of BBI608 and TMZ. Collection, 
storage, and shipping of PK samples will be performed as described in the Laboratory 
Manual at time points outlined below: 


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Day
Procedure
Sample 
No.
Desired Time
1
Draw blood sample
PK-01
0 hr (pre-dose)
First daily  BBI608 dose
0
Draw blood sample
PK-02
0.5 hr
Draw blood sample
PK-03
1 hr
Draw blood sample
PK-04
2 hr
Temozolomide Administrationa
3 hr
Draw blood sample
PK-05
3 hr
Draw blood sample
PK-06
4 hr
Draw blood sample
PK-07
5 hr
Draw blood sample
PK-08
7 hr
Draw blood sample
PK-09
10 hr
Draw blood sample
PK-10
12 hr
Day
Procedure
Sample 
No.
Desired Time
5
Draw blood sample
PK-11
0 hr (pre-dose)
First daily BBI608 dose
0
Draw blood sample
PK-12
0.5 hr
Draw blood sample
PK-13
1 hr
Draw blood sample
PK-14
2 hr
Temozolomide Administrationa
3 hr
Draw blood sample
PK-15
3 hr
Draw blood sample
PK-16
4 hr
Draw blood sample
PK-17
5 hr
Draw blood sample
PK-18
7 hr
Draw blood sample
PK-19
10 hr
Draw blood sample
PK-20
12 hr
aTemozolomide will be administered 3 hours after BBI608 during PK assessments
6.5
Pharmacodynamic Assessments  
Pre-clinical and clinical studies conducted by BBI have identified several biomarkers in 
tumor tissues whose levels either increase or decrease upon exposure to BBI608.  Archival 
tumor samples will be collected from patients in both study arms. On-study tumor samples 
following 1 week of treatment with BBI608 monotherapy prior to surgical resection will be 
collected ONLY from patients enrolled into Arm A, as described below. The goal of the 
proposed biomarker study is to examine the response of biomarkers in patients treated with 
BBI608 monotherapy. Subject tumor samples will be processed for determination of 
pharmacodynamic markers in malignant tissue by histopathology and cancer stem cell (CSC) 
assays. 


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6.6
Archival and On-Study Tumor Tissue Collection  
Archival formalin fixed paraffin-embedded (FFPE) tissue samples from a previous resection 
or biopsy of the patient’s glioblastoma should be collected from all patients enrolled in the 
clinical trial. 
For patients enrolled into Arm A, the archival tumor tissue will serve as a baseline sample 
prior to starting treatment with BBI608.  An on-treatment tumor sample will be collected 
during the surgical tumor resection, following completion of the 1-week BBI608 
monotherapy treatment.  
Tumor samples that are obtained at the time of surgical resection and are labeled with study 
protocol identification number and patient identification number will be sent to a regulatory 
authority-approved tumor bank affiliated with the study site, or to the study site pathology 
department if the site does not have a regulatory authority-approved tumor bank. 
Appropriately processed tumor specimens would be then forwarded to the Sponsor or 
Sponsor CRO for analysis. Processing of all tumor tissue will include creation of both fresh 
frozen samples for PK analysis as well as blocks of formalin fixed paraffin-embedded 
(FFPE) samples for PD analysis.  
Collection, storage, and shipping of tissue samples will be performed as described in the 
accompanying Laboratory Manual.  
Other investigations on tumor samples may be performed as determined by the study 
investigators and/or study sponsors.  If the patient grants permission, tumor samples may be 
stored for additional future studies.   
Please see the Laboratory Manual for this study for more information regarding collection, 
processing, storage and shipment of tumor sample tissue. 
7
TREATMENT 
7.1
BBI608 
BBI608 capsules will be supplied to the pharmacy at the clinical sites.  Study drug will be 
labeled as an investigational agent, limited by federal law.  The pharmacist will dispense an 
appropriate number of each strength capsule to the Principal Investigator for in-clinic dosing.  
The appropriate quantity of capsules will be dispensed to the patient for each cycle (see 
Section 5.4 and Appendices A and B).  
BBI608 is supplied as 80 mg capsules and should be stored at room temperature (15-25 
degrees Celsius).
These instructions must appear on the label for the container in which 
capsules are delivered to the patient.   
7.1.1
Investigational Product Accountability 


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BBI will provide all study drug required for completion of this study.  The recipient will 
acknowledge receipt of the drug indicating shipment content and condition.  Damaged 
supplies will be replaced.  Until dispensed to the patients, the 80 mg capsules will be stored 
in a temperature controlled, secure locked area, accessible to authorized personnel only, at 
room temperature (15-25 degrees Celsius). 
Accurate records of all study drug dispensed from and returned to the study site are to be 
maintained.  The study site must supply a copy of their drug destruction policy to BBI before 
authorization for destruction will be granted.  Product accountability will be monitored 
throughout the study.  Upon completion or termination of the study, and after inventory by a 
BBI monitor or designated representative, all unopened drug is to be returned to BBI, or 
designee, in the original containers.  
7.1.2
BBI608 Administration 
BBI608 will be administered continuously by mouth twice daily, with doses approximately 
12 hours apart.  BBI608 should be administered approximately one hour prior to or two hours 
after meals, and the first dose should be given in the morning.   
The dose of BBI608 to be administered depends on the dose level to which the patient is 
enrolled.  See Section 4.1 for details. 
7.1.3
Temozolomide (TMZ) Administration 
Detailed instructions for the preparation, premedication, and administration of TMZ are 
provided in the Product Labels approved by Health Canada or US FDA. Temozolomide is a 
standard of care medication and will not be provided by the Sponsor. 
TMZ 150 mg/m2 will be administered orally to patients enrolled into arms A and B, 
beginning on Day1 of Cycle 1 of combination treatment.  TMZ will be administered on days 
1 through 5 of each 28-day combination therapy cycle. In case of toxicity, dose adjustment is 
permitted. If TMZ is tolerated at the 150 mg/m2 once daily dose, dosage may be increased to 
200 mg/m2 once daily dose after the first cycle. 
A 3 hour interval between the first daily dose of BBI608 and the initiation of TMZ is 
required on PK days (i.e. C1D1 and C1D5) during Cycle 1 only, in order to standardize PK 
interpretation. On all other days, the first daily administration of BBI608 should precede the 
administration of TMZ by 0-4 hours. 
7.2
Dose Modifications 
7.2.1
BBI608 
For any suspected BBI608-related grade 3 or intolerable grade 2 adverse events that persist 
despite optimized medical management (see Table 1), a dose holiday of 0.5-3 days followed 
by dose modification as outlined in the table below is recommended. Investigators should 


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discuss dose modifications with the Medical Monitor for the Sponsor. Patients should up-
titrate dose with the goal of achieving full dose as tolerated. 
Suggested Management for AEs Associated with BBI608 Administration 
BBI608 Dose Modification Table: 
Suspected BBI608 -Related 
Adverse Event
Investigator Action
Grade 1 or tolerable Grade 2 
Symptoms
xPatient should remain at current dose. Attempt pharmacologic
measures to minimize symptoms (see Table 1 below). 
Intolerable Grade 2 Symptoms
xIf intolerable symptoms persist despite optimized medical 
management, dose reduction and sufficient oral hydration 
are recommended. A dose interruption of ½ to 3 days prior 
to reduction can also be considered. 
xDosing should be reduced to the next Modification Level on 
the dose modification table. Pharmacologic symptom 
support and/or prophylaxis should be maintained (see Table 
1).
xAfter a dose reduction, AM and PM doses may be increased in 
80 mg increments every 3-7 days as tolerated.*, **
Grade 3 or 4 Symptoms
xA dose interruption of ½ to 3 days is recommended until 
symptoms are reduced to ≤ grade 2. 
xDosing should be reduced to the next Modification Level on 
the dose modification table. Pharmacologic symptom 
support and/or prophylaxis should be maintained (see Table 
1).
xAfter a dose reduction, AM and PM doses may be increased
in80 mg increments every 3-7 days as tolerated.*, **
*
If, during the course of re-escalation, a dosing regimen is not tolerated despite optimized medical management, 
dosing should return to the highest previously tolerated dosing regimen.
** Asymmetry between AM and PM dose is allowed during re-escalation (e.g. 320 mg AM/240 mg PM).
Dose Level
Dose
Full dose
480 mg twice daily (q12h)
Modification Level-1
240 mg twice daily (q12h), up titrate as tolerated**
Modification Level-2
80 mg twice daily (q12h), up-titrate as tolerated**
Modification Level-3
80 mg once daily*, up-titrate as tolerated**
*
If 80 mg once daily is not tolerated, a dose interruption of 1-3 days followed by re-challenge at 80 mg once daily is 
recommended.
**
Morning and evening doses can be increased in 80 mg increments every 3-7 days or slower as tolerated, up to 480   
mg two times daily. 


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Table 1: Supportive Pharmacology for Adverse Events Associated with BBI608 Administration 
Diarrhea & Abdominal Cramping 
 
Nausea, Vomiting, or Anorexia 
 
 
 
Dicyclomine (e.g., Bentyl): Recommended when the 
predominant issue is cramping or abdominal pain 
 
1st line: 5HT3-inhibitors (Ondansetron, 
Palonosetron, Granisetron) 
Diphenoxylate/atropine (Lomotil) 
 
Loperamide (Imodium) 
These agents 
may be 
particularly 
useful in 
combination 
 
2nd line:  Dexamethasone (Decadron), ideally in 
combination with a 5HT3-inhibitor.  Short term 
use can be very effective 
Systemic opioids (e.g. Dilaudid, Codeine): have been 
found effective in reducing abdominal pain and watery 
diarrhea 
 
Other  agents: anti-histamines, benzodiazepines, 
proton pump inhibitors/H2 antagonists, 
dopamine antagonists, and cannabinoids 
Hyoscine (Buscopan, Scopolamine, Levsin):  Anti-
spasmodic agents helpful for abdominal cramping 
 
Budesonide (Entocort EC): Topical Corticosteroid with 
limited systemic absorption; 9mg PO once daily for 8 to 
12 weeks 
 
It is recommended adding Budesonide prophylaxis to improve GI tolerability of BBI608. 
Start prophylactic Budesonide 9mg QD PO, 24 hours prior to the first dose of BBI608 on Cycle 1, Day 
1. Take Budesonide at least 2 hours apart from BBI608 and TMZ, either before or after taking BBI608 
and TMZ.   Continue to take Budesonide for 8 to 12 weeks. 
7.2.2
Temozolomide 
Serious toxicities attributable to TMZ include neutropenia, thrombocytopenia, lymphopenia, 
pneumocystis pneumonia, and hepatotoxicity.  Common adverse side-effects of TMZ include 
nausea and vomiting. Please see the Package Insert for full prescribing and toxicity 
information. 
Cycle 1: Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 
23 days without treatment. Cycles 2-6: 
At the start of Cycle 2, the dose can be escalated to 200 mg/m2 , if the CTC non-hematologic 
toxicity for Cycle 1 is Grade less than or equal to 2 (except for alopecia, nausea, and 
vomiting), absolute neutrophil count (ANC) is greater than or equal to 1.5 x 109 /L, and the 
platelet count is greater than or equal to 100 x 109 /L.  


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The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except 
if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in 
subsequent cycles.  
Dose Reduction or Discontinuation:  
Dose reductions should be applied according to Tables 2 and 3.  
During treatment, a complete blood count should be obtained on Day 22 (21 days after the 
first dose of TEMODAR) or within 48 hours of that day, and weekly until the ANC is above 
1.5 x 109 /L (1500/μL) and the platelet count exceeds 100 x 109 /L (100,000/μL).  
The next cycle of TEMODAR should not be started until the ANC and platelet count exceed 
these levels. Dose reductions during the next cycle should be based on the lowest blood 
counts and worst non-hematologic toxicity during the previous cycle.   
Dose discontinuations should be applied according to Tables 2 and 3. 
Table 2:  Temozolomide Dose Levels for Maintenance Treatment 
 
Table 3:  Temozolomide Dose Reduction or Discontinuation During Maintenance 
Treatment 
Toxicity 
Reduce TMZ by 1 Dose Level* 
Discontinue TMZ 
Absolute Neutrophil Count 
Less than 1.0 x 10 
See footnote† 
Platelet Count 
Less than 50 x 10 
See footnote† 
C Nonhematological Toxicity (except for 
alopecia, nausea, vomiting) 
CTC Grade 3 
CTC Grade 4 
 
*TMZ dose levels are listed in Table 2.  
† TMZ is to be discontinued if dose reduction to less than 100 mg/m2 is required or if the same Grade 
3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. 
TMZ=temozolomide; CTC=Common Toxicity Criteria. 
Dose modifications for toxicities attributed to TMZ should be performed according to 
institutional standards or as per Product Labels approved by Health Canada or US FDA (see
Package Insert,). Dose Modification instructions taken from the US Package Insert appear 
below in Figure 1 for reference: 
Dose Level 
Dose (mg/m²/day) 
Remarks 
-1 
100 
Reduction to prior toxicity 
0 
150 
Dose during Cycle 1 
1 
200 
Dose during Cycles 2-6 in absence of toxicity 


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Figure 1 Dose Modification Instructions for Temozolomide 
If a toxicity is thought by the Investigator to be related to both BBI608 and TMZ 
combination regimen, then the dose modification rules for both BBI608 and temozolomide 
should be followed. 
7.2.3 Overlapping Toxicities  
Nausea, vomiting, anorexia and diarrhea are frequent AEs that could be attributed to both 
drugs independently. The temporal course may help to determine the attribution to a 
particular drug. If both drugs are considered to be the cause of these AEs, the 
recommendations are to follow dose modifications for BBI608 and temozolomide, as 
indicated above.  
7.2.4 Start of a new Cycle
Drug(s) will be resumed once all toxicities have recovered to Grade <2. 
7.3
Treatment Compliance 
A patient is considered compliant with the study protocol when he or she takes at least 80% 
of both the assigned study medication and TMZ. Treatment compliance will be monitored via 
Patient Diary in order to verify the Per Protocol patient population. 


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BBI608 and TMZ compliance will be calculated using the following equation: 
7.4
Blinding 
This is an open label study. Neither the patient nor the investigator and site staff will be 
blinded to the treatment administered. 
7.5
Prior Treatment 
Reasonable efforts will be made to determine all relevant prior treatments received by the 
patient. All relevant information must be recorded on the appropriate patient's Case Report 
Form (CRF). All surgical procedure history, prior chemotherapy, and radiation therapy must 
be recorded on the appropriate CRF. 
7.6
Concomitant Medication 
7.6.1
Permitted Treatment 
All information regarding concomitant treatments (medications or procedures) must be 
recorded on the patient’s CRF (including the name of the medication or procedure and 
duration of treatment).  
Concurrent corticosteroid administration is permitted as specified in the inclusion criteria. 
Any corticosteroid administration must be recorded on the patient’s CRF. Steroid dosing will 
be adjusted as clinically appropriate during therapy.
Palliative and supportive care for disease-related symptoms will be offered to all patients in 
this study.   
BBI608 was shown in vitro to inhibit individual CYP P450 isoforms 1A2, 2D6, 2C19, 3A4, 
and 2C9 with IC50’s of 0.25 μM, 0.25 μM, 2.5 μM, 5 μM, and 0.5 μM respectively, under 
serum-free conditions. Since BBI608 has shown the ability to inhibit these CYP P450 
isoforms in vitro, concomitant use of agents that are substrates of these CYP P450 enzymes 
should be used only if deemed medically necessary by the primary investigator. Examples of 
commonly prescribed agents that are metabolized by these CYP P450 enzymes are: 
 NSAIDS: such as ibuprofen, naproxen 
Proton pump inhibitors: such as lansoprazole, omeprazole  
Oral hypoglycemic medications: sulfonylureas  
Beta-blockers: metoprolol, carvedilol  
Calcium channel blockers: amlodipine, diltiazem, nefedipine, verapamil  
Antidepressants: paroxetine, imipramine, amitriptyline  
Anti-epileptics: such as phenytoin, phenobarbitone  
Anti-psychotics: such as haloperidol, risperidone  
Antibiotics: such as clarithromycin, erythromycin  


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HMG CoA reductase inhibitor: atorvastatin, lovastatin, simvastatin  
Anesthetics: such as halothane, enflurane; 
HIV antivirals: such as saquinavir, indinavir, ritonavir  
Immunomodulators (immunosuppressives): such as cyclosporine, tacrolimus 
Steroids: such as hydrocortisone, estrodiol 
BBI608 is metabolized by the CYP P450 isoform 1A2. Therefore, concomitant use of drugs 
that inhibit or induce CYP1A2 should be avoided unless deemed medically necessary by the 
primary investigator.   
Known drugs that inhibit CYP 1A2 include ciprofloxacin and other fluoroquinolones, 
Fluvoxamine Verapamil, amiodarone, interferon, methoxsalen, enoxacin, mexiletine, and 
ticlopidine.
Several common anti-epileptic drugs are known to induce CYP1A2 including 
carbamazepine, phenobarbital and phenytoin. These enzyme-inducing anti-epileptics 
(EIAEDs) should be avoided with concomitant BBI608 treatment, and a non-AEID 
alternative anti-convulsant should be used instead. 
Of note, no clinically apparent drug-drug interactions occurred during phase I or phase Ib/II
studies conducted with BBI608 thus far. 
In addition, the following treatments are allowed: 
x
Standard therapies for concurrent medical conditions 
x
Epoetin alfa (Epogen®, Procrit®)
x
Hematopoietic growth factors, including filgrastim (Neupogen®), or other granulocyte 
colony stimulating factors (G-CSF), are permitted following documented and 
clinically significant neutropenia after the patient has completed at least one cycle of 
treatment with BBI608 
x
Prophylactic antiemetics may be administered according to standard practice  
x
Low dose corticosteroids used as an antiemetic regimen 
x
Megestrol acetate (Megace®)
7.6.2
Budesonide - Interaction with CYP3A4 inhibitors 
Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in 
the liver and in the intestinal mucosa) caused an eight-fold increase of the systemic exposure 
to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, 
itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of 
budesonide should be considered. After extensive intake of grapefruit juice (which inhibits 
CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral 
budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be 
avoided in connection with budesonide administration. 


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7.6.3
Prohibited Treatment 
x
Any concurrent chemotherapy, radiotherapy, hormonal therapy, or immunotherapy;
palliative radiotherapy for non-target lesions may be permitted in certain cases as 
decided by the principal investigator and sponsor 
x
Other investigational agents 
x
CYP1A enzyme-inducing antiepileptic drugs (including phenobarbital, phenytoin, 
and carbamazepine)  
x
Immunosuppressive therapies, including systemic corticosteroids (except when used 
intermittently, such as in an antiemetic regimen, or when used for GBM)
8
SAFETY ASSESSMENTS 
8.1
Adverse Events  
8.1.1
Assessments 
The Investigator is responsible for monitoring the safety of patients who have enrolled in the 
study. All AEs considered to be related to BBI608 occurring after any administration of the 
study drug will be followed until the event resolves. AEs will be evaluated using the National 
Cancer Institute (NCI) CTCAE, Version 4.0.
Investigators are required to document all AEs occurring during the clinical trial, 
commencing with study enrollment and including the protocol-defined post-treatment 
follow-up period (21 Code of Federal Regulations [CFR] §312.64[b]) on designated CRF 
pages. It is also important to record all AEs that result in permanent discontinuation of the 
investigational product being studied, whether serious or non-serious. 
Serious adverse events (SAEs), as defined below, must be reported to Boston Biomedical or 
its representative within 24 hours of knowledge of their occurrence. 
8.1.2
Definitions 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject that does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal product. 
Laboratory data are to be collected as stipulated in this protocol, and toxicity trends will be 
analyzed utilizing objective toxicity criteria.  Clinical syndromes associated with laboratory 
abnormalities are to be recorded as appropriate (e.g., diabetes mellitus instead of 
hyperglycemia).   
Progression of disease is considered an efficacy outcome parameter and should not be 
captured as an AE.  A non-serious AE is any untoward medical occurrence that does not 
meet any of the criteria for SAEs as defined below. 
Patients should be instructed to report any AE that they experience to the Investigator.  
Investigators should assess the patient for AEs at each visit.  AEs occurring during the 
clinical trial and the follow-up period should be recorded on the appropriate AE CRF.  To 


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capture the most potentially relevant safety information during a clinical trial, it is important 
that investigators record accurate AE terms on CRFs. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the CRF.  However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the investigator, it should be recorded as a separate AE on the CRF. 
8.2
Serious Adverse Events 
8.2.1
Definitions 
A serious adverse event (SAE) is any adverse event occurring at any dose that results in any 
of the following outcomes: 
x
Death 
x
A life-threatening adverse drug experience 
x
Inpatient hospitalization or prolongation of existing hospitalization   
x
A persistent or significant disability/incapacity 
x
A congenital anomaly/birth defect 
Important medical events may be considered an SAE based upon appropriate medical 
judgment.   
Under this protocol, scheduled hospitalizations or elective surgical/medical procedures or 
elective hospitalization will not be considered SAEs.  Prolongation of a scheduled 
hospitalization can be considered an SAE.  Complications associated with scheduled 
procedures are considered an AE. 
8.2.2
Reporting Serious Adverse Events 
Any SAE, including death, due to any cause that occurs during this investigation, whether or 
not related to the administration of study drug, must be reported to the Sponsor immediately 
(not to exceed 24 hours) by telephone, secured email or facsimile.  The reaction must be 
completely d escribed on the CRF and SAE report form. 
Primary Medical Monitor Contact 
information:
Waldo Ortuzar, MD
640 Memorial Drive
Cambridge, MA 02139
Telephone: (617) 674-6800 ext 8722
Fax: (617) 674-8662
Email: wortuzar@bostonbiomedical.com 
Emergency Number: 317-695-0792


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9
ASSESSMENT OF ANTI-TUMOR ACTIVITY 
The following definitions and criteria (from Response Assessment in Neuro-Oncology 
[RANO Wen et al., 2010] Working Group criteria) should be used for the baseline 
evaluations of existing disease, and for the ongoing evaluation of tumor responses. 
Measurable disease - presence of at least one measurable lesion.  
Measurable lesions - lesions that are bidimensionally contrast-enhancing with clearly 
defined margins by CT or MRI scan, with two perpendicular diameters of at least 10 mm, 
visible on two or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip. 
The size of a measurable lesion at baseline should be two times the slice thickness. 
Non-measurable lesions - all other lesions, including small lesions (longest perpendicular 
diameters < 10 mm), unidimensionally measurable lesions, or masses with margins not 
clearly defined. 
x
All measurements should be taken and recorded in metric notation, using a 
ruler or calipers. 
x
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.
x
Tumor surrounding a cyst or a surgical cavity should be considered non-
measurable unless there is a nodular component measuring > 10 mm in 
diameter.  
9.1
Method of Measurement 
x
MRI (T1-weighted contrast-enhanced images as well as T2-weighted/FLAIR 
images) is the best currently available and reproducible method to measure 
target lesions selected for response assessment.  Conventional MRI should be 
performed with cuts of 5 mm or less in slice thickness contiguously.   
x
CT scan with contrast enhancement may be used for patients with MRI non-
compatible devices. 
x
All imaging methods should be performed according to institutional standards 
with each patient having consistency of methods beginning from baseline 
through the course of the study. 
x
Ideally patients should be imaged on the same MRI or CT (for patients with 
MRI non-compatible devices), or at least with the same magnet strength, for 
the duration of the study to reduce difficulties in interpretation of images. 
9.2
Baseline Documentation of “Target” and “Non-Target” Lesions 
x
If there are multiple contrast-enhancing lesions, a minimum of two lesions up 
to a maximum of five lesions total should be identified as target lesions and 
recorded and measured at baseline. 


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x
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). 
x
Occasionally, the largest lesions may not allow reproducible repeated 
measurements, and the next largest lesions that can be measured reproducibly 
should be selected. 
x
A sum of the products of the perpendicular longest diameters (LD) for all 
target lesions will be calculated and reported as the baseline sum LD.  The 
baseline sum LD will be used as the reference by which to characterize the 
objective tumor response. 
x
Patients with multiple lesions of which only 1 or 2 are increasing in size, the 
enlarging lesions should be considered the target lesions for evaluation of 
response. The other lesions will be considered non-target lesions and should 
also be recorded.    
x
The cystic or surgical cavity should not be measured for response 
determination. 
x
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.
9.3
Response Criteria 
Radiographic response should be determined in comparison to the tumor measurement 
obtained at pretreatment baseline for determination of response, and the smallest tumor 
measurement at either pretreatment baseline or after initiation of therapy for determination of 
progression. For patients in Arm A who undergo surgical resection, the post-operative 
baseline scan (performed 48-72 hours after surgery) should be used for response assessment. 
Response criteria are outlined below. In the event that the radiographic changes are equivocal 
and it is unclear whether the patient is stable or has developed progressive disease, it is 
permissible to continue treatment and observe the patient closely, for example at 4-week 
intervals. If subsequent imaging studies demonstrate that progression has occurred, the date 
of progression should be the date of the scan at which progression was first suspected.  
Complete Response* 
Requires ALL of the following: 
1. Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. 
2. No new lesions. 
3. Stable or improved non-enhancing (T2/FLAIR) lesions. 
4. Patients must be off corticosteroids (or on physiologic replacement doses only). 
5. Patients must be stable or improved clinically.#
Partial Response* 


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Requires ALL of the following:
1. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 
weeks.  
2. No progression of non-measurable disease.  
3. No new lesions.  
4. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
5. The corticosteroid dose at the time of the scan evaluation should be no greater than 
the dose at time of baseline scan. 
6. Patients must be stable or improved clinically.#
Stable Disease 
Requires ALL of the following: 
1. Does not qualify for complete response, partial response, or progression. 
2. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. IN the event that the corticosteroid dose was increased for 
new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered 
to show stable disease will be the scan obtained when the corticosteroid use was 
equivalent to the baseline dose. 
3. Patients must be stable clinically.#
Progressive Disease 
Defined by ANY of the following: 
1. Greater than 25% increase in the sum of the products of perpendicular diameters of 
enhancing lesions compared to the smallest tumor measurement obtained either at 
baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids.** 
2. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses 
of corticosteroids compared to baseline scan or best response following initiation of 
therapy,* not due to co-morbid events (e.g. radiation therapy, demyelination, 
ischemic injury, infection, seizures, post-operative changes, or other treatment 
effects).  
3. Any new lesion. 
4. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.) or changes in corticosteroid dose.#
5. Failure to return for evaluation due to death or deteriorating condition. 
6. Unequivocal progression of non-measurable disease. 
*Patients with non-measurable disease only cannot have a complete or partial response. The 
best response possible is stable disease. 
**Stable doses of corticosteroids include patients not on corticosteroids. 


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#Clinical status will be assessed via ECOG Performance Score. 
9.4
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence and is determined as indicated in the table below: 
The table below provides the summary of the RANO response criteria.  
Criterion
Complete 
Response
Partial 
Response 
Stable Disease
Progressive 
Disease
T1/Gd 
enhanced 
lesions
None
>50% decrease
<50% decrease 
to <25% 
increase
>25% increase*
T2/FLAIR
Stable or 
decreasing
Stable or 
decreasing
Stable or 
decreasing
Increasing*
New Lesion
None
None
None
Present*
Corticosteroids
None
Stable or 
decreasing
Stable or 
decreasing
NA**
Clinical 
Status#
Stable or 
improving
Stable or 
improving
Stable or 
improving
Worsening*
Requirement 
for Response
ALL
ALL
ALL
Any*
*Progressive Disease occurs when any of the criteria marked by * are present. 
**Increase in corticosteroid dose in isolation of other criteria will not be taken into account 
in the assessment of progressive disease in the absence of persistent clinical status 
deterioration. 
#Clinical status will be assessed via ECOG Performance Score  


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10 PLANNED STATISTICAL METHODS 
10.1 General Considerations 
Categorical variables will be summarized as the number and percentage of patients in each 
category. Continuous variables will be summarized by the mean, standard deviation, median, 
minimum, and maximum. 
The primary population for the efficacy endpoints will be the Per Protocol population defined 
as the population of patients who have been treated with at least 80% of 1 complete cycle of
BBI608 and TMZ. Analyses will also be performed on   the Intent-to-Treat (ITT) population 
in each arm. The primary endpoint is PFS-6, defined as the proportion of patients with PFS 
(i.e. absence of documented objective progression or death) at 6 months after enrollment.   
For each of the study arms, the secondary endpoints will include OS, defined as the interval 
between the date of patient enrollment until death; PFS, defined as the interval between the 
date of patient enrollment and objective disease progression or death; ORR, the proportion of 
patients with a documented complete response or partial response according to the RANO 
criteria; and DCR, the proportion of patients with a documented stable disease, partial 
response or complete response according to RANO criteria. 
10.2 Determination of Sample Size 
For each of the study arms, with the a sample size of 30, the lower bound of the two-sided 
80% confidence interval, as estimated by the exact binomial method using a projected PFS-6 
of 20%, will be greater than 10%, and provides meaningful information for further clinical 
evaluation. 
10.3 Analysis Populations 
All patients receiving at least one dose of BBI608 will be considered evaluable for safety 
analysis.  Adverse event incidence rates will be described by the frequency of adverse events, 
categorized by NCI CTCAE version 4.0.  Listings of laboratory test results collected at 
baseline and during the study will be generated.  Descriptive statistics summarizing the 
changes in those laboratory tests over time will be presented. 
For each of the study arms, the primary population for the efficacy endpoints will be the Per 
Protocol population defined as the population of patients who have been treated with at least 
80% of 1 complete cycle of BBI608 and TMZ. Analyses will also be performed on   the 
Intent-to-Treat (ITT) population in each arm. The primary endpoint is PFS-6, defined as the 
proportion of patients with PFS (i.e. absence of documented objective progression or death) 
at 6 months after enrollment.   
10.4 Demographics and Baseline Characteristics 
Patient characteristics will include a summary of the following: 


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x
Patient demographics 
x
Baseline disease characteristics 
x
Pre-existing conditions 
x
Prior therapies 
x
Concomitant medications and treatments 
x
MGMT methylation status 
Other patient characteristics will be summarized as appropriate 
10.5 Statistical Analysis of Pharmacokinetic Variables 
Timed blood sample collection for pharmacokinetic analysis will be performed on Days 1 
and 5 of Cycle 1 of combination treatment with BBI608 and TMZ for Phase Ib/DLT cohort 
patients in each study arms. 
Timed blood sample collection for pharmacokinetic analysis will additionally be performed 
for patients who experience a dosing regimen modification.   
These sample collections will be according to the parameters outlined in Sections 6.4, and the 
accompanying study Laboratory Manual.
Bioanalytical analysis of patient samples will be conducted at a centralized laboratory using 
GLP-validated assays.  Plasma concentrations will be summarized by descriptive statistics, 
including mean, standard deviation, coefficient of variation, minimum, maximum, and 
median.
Concentration profiles will be analyzed by non-compartmental and/or non-linear least 
squares regression using WinNonLin.  Pharmacokinetic parameters, including Cmax, volume 
of distribution, distribution half-life, terminal half-life, and AUC will be evaluated.  
10.6 Safety Analysis 
Safety will be assessed by physical examination, and laboratory assessments.  Weekly 
laboratory testing is required during the first 2 cycles of Phase Ib. Adverse events will be 
graded according to the NCI CTCAE, version 4.0.  The incidence of DLTs will be evaluated 
for in all patients enrolled into a safety cohort for each of the study arms.  The incidence of 
adverse events will be evaluated for all patients. All patients will be followed for adverse 
events for at least 30 days after the last dose of BBI608, or until recovery from all study drug 
related adverse events.  
11 QUALITY CONTROL AND ASSURANCE 
The study will be initiated and conducted under the sponsorship of Boston Biomedical.  
Study drug, clinical supplies, and CRFs will be supplied by Boston Biomedical, or its 
representative.  Representatives of Boston Biomedical will monitor the study to verify study 
data, medical records, and CRFs in accordance with current ICH GCPs and other applicable 
regulations and guidelines. 


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11.1 Compliance with the Protocol 
The Investigator will notify the Sponsor of any deviations from the protocol.  Such contact 
with the Sponsor will be made as soon as possible to permit a decision as to whether or not 
the subject (for whom the deviation from the protocol was effected) is to continue in the 
study.  The case records will describe the deviation from the protocol and state the grounds 
for it. 
11.2 Registration and Enrollment 
This is an open-label, non-randomized study.  Boston Biomedical should be notified as soon 
as a subject qualifies for entry in the protocol.  Subjects will be registered by faxing Boston 
Biomedical or their designee, within 10 days prior to the 1st drug administration.  The subject 
will be enrolled into the study when the subject receives the 1st dose of study drug.  
Registration and enrollment forms and faxing instructions will be provided with the Case 
Report Forms (CRFs).  The site should maintain a log of all subjects who are screened (i.e., 
who sign consent) but do not qualify for the study, or who do not receive study drug.  The 
reason for disqualification should be noted in the log. 
11.3 Removal, Replacement, or Early Withdrawals of Subjects 
If a subject exits the study prior to receiving 28 days of combination treatment study drug 
with TMZ or does not receive 28 days of combination treatment study drug with TMZ for a 
reason other than DLT, an additional subject may be recruited to replace the subject. 
12 COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL 
 
CONSIDERATIONS AND INFORMED CONSENT 
12.1  Institutional Review Board 
 
 
The protocol, any protocol modifications, informed consent form that will be used, 
and, if applicable, the permission to use private health information must be approved 
by the Investigator’s IRB or Independent Ethics committee (IEC) before the study is 
initiated.  Documentation of this approval (i.e., a copy of the document showing 
IRB/IEC approval including the chairperson’s signature and the date of approval) 
must be provided to Boston Biomedical or its designee, and made available during an 
inspection by the FDA or other regulatory agency inspectors.  The Investigator will 
submit to Boston Biomedical: 
-
A list of the names, occupations, and affiliations of the members of the IRB 
-
Documentation that the IRB is duly constituted or a General Assurance 
Number 
-
No supplies will be shipped until the IRB has given written approval of the 
protocol and informed consent and Boston Biomedical has received copies of 
the approvals 
It is the responsibility of the Investigator to: 


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-
Submit to the IRB/IEC for review any advertisements that will be used to 
recruit subjects 
-
During the conduct of the study, submit progress reports to the IRB, if 
required, and request review of the study  
-
Report, in writing, to the IRB all SAEs that occurred during the study or SAEs 
reported in other studies using study drug, per local IRB regulations 
-
Inform the IRB of any changes in the protocol and obtain documented IRB 
approval of the changes 
-
Maintain a file of study-related information, including all correspondence with 
the IRB/IEC 
-
Within 3 months of study completion, provide the IRB with a final report on 
the study 
12.2  Compliance with Good Clinical Practice and Ethical Considerations 
This study must be conducted in compliance with IRB/IEC informed consent 
regulation and the ICH GCP Guidelines.  In addition, all local regulatory 
requirements will be adhered to, in particular those which afford greater protection to 
the safety of the trial participants. 
This study will be conducted according to the current revision of the Declaration of 
Helsinki (Revised Edinburgh, Scotland, 2000) and with local laws and regulations 
relevant to the use of new therapeutic agents in the country of conduct. 
Before initiating a trial, the Investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the trial protocol/amendment(s), 
written informed consent form, patient recruitment procedures (e.g., advertisements) 
and written information to be provided to patients. 
Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an 
immediate hazard(s) to patients. 
12.3 
Informed Consent and Permission to Use Private Health Information 
The Investigator, or designee, is responsible for the content of the informed consent 
form, but the content must be submitted and approved by Boston Biomedical, prior to 
submission to the IRB.  Before the start of required study procedures, the Principal 
Investigator or associate must obtain informed consent from each study participant (or 
the subject’s parent/guardian) in accordance with ICH document “Guidance for 
Industry – E6 Good Clinical Practice: Consolidated Guidance” dated April 1996.  It 
should also include any additional information required by local laws relating to 
institutional review. 
Informed consent must be obtained from the subject before any screening activity, 
washout of medication, or treatment (that is not part of routine care) is undertaken.  
Informed consent will be obtained by discussing with the subject the purpose of the 


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study, the risks and benefits, the study procedures, and any other information relevant 
to the subjects. 
The subject or his/her legal representative will document their informed consent by 
signing the current version of the written, IRB-approved, informed consent form in 
the presence of a witness. 
The person, who conducted the informed consent discussion with the subject and/or 
guardian, must also sign the informed consent form.  The subject should be given a 
copy of the informed consent form with all of the appropriate signatures. 
The Principal Investigator will ensure that a copy of the signed consent is kept with 
the Clinical Trial Master File. 
The Investigator or designee must explain to the patient subject that for evaluation of 
study results, that subject’s private health information obtained during the study may 
be shared with the study Sponsor, regulatory agencies, and ECs/IRBs, before 
enrolling that subject into the study. It is the Investigator’s (or designee’s) 
responsibility to obtain permission to use private health information from each 
subject, or if appropriate, the subject’s legal guardian.
 
13  STUDY MANAGEMENT 
13.1  Amendments to the Protocol 
Once the protocol has been approved by the IRB, the Investigator will not modify it 
without obtaining the prior concurrence of Boston Biomedical.  In turn, Boston 
Biomedical will inform the Investigator in writing of any amendment to the protocol.  
The Investigator must submit the protocol modifications and any informed consent 
modifications to the IRB, and approval must be obtained before the modifications are 
implemented.  Boston Biomedical will submit protocol modifications to the US FDA, 
Health Canada, or other appropriate Regulatory Agencies. 
13.2  Investigator Brochure and Information Materials 
Before the study begins, the Investigator will receive an Investigator’s Brochure 
describing all known contraindications, warnings, precautions, and adverse reactions 
associated with the administration of the study drug.  If such information is revised 
while the study is in progress, the brochure will be amended or revised, and Boston 
Biomedical will provide the most current version to the Investigator. 
13.3  Pre-investigational Documents 
Prior to the shipment of the study drug(s), the Investigator will supply Boston 
Biomedical with the following: 
-
A signed Investigator Clinical Research Agreement 
-
A completed Form FDA 1572 signed by the Investigator 


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-
Current curricula vitae and copy of current medical license for the Principal 
Investigator and Sub-Investigators listed on Form FDA 1572 
-
A completed financial disclosure form for all personnel listed on Form FDA 
1572
-
Signed and dated protocol signature page by the Principal Investigator 
-
A copy of the approval for this protocol from the IRB listed on Form FDA 
1572
-
A copy of the approval for the informed consent from the IRB listed on Form 
FDA 1572 
-
A copy of the IRB-approved informed consent 
-
Evidence of laboratory certification and a list of laboratory normal ranges for 
all laboratories listed on Form FDA 1572 
-
A list of the IRB members (for the IRB on Form FDA 1572) and the member 
occupations and affiliations; written verification that the IRB is duly 
constituted or the General Assurance Number 
13.4  Drug Inventory Record 
The Investigator, or a responsible party (research pharmacist or other) designated by 
the Investigator, must maintain an inventory record of drug received and dispensed.  
Boston Biomedical will provide forms to facilitate the inventory control.  These forms 
must be used unless the Investigator has previously established a system that 
complies with FDA and/or Health Canada regulations and is approved by Boston 
Biomedical.  The study drug must be dispensed only to the institution(s) specified on 
form FDA 1572. 
13.5  Disposition of Used and Unused Study Drug 
Upon completion or termination of the study and after inventory by a Boston 
Biomedical monitor or designated representative, all unopened drugs are to be 
returned to Boston Biomedical in the original containers.  All used vials will be 
retained until released for destruction by the Boston Biomedical monitor. Unopened 
returned drugs, with completed Boston Biomedical forms for return shipment, should 
be shipped as instructed by the Sponsor. 
13.6  Study Records 
Boston Biomedical will provide the Investigator with drug shipment records, CRFs 
designed to collect the data specified for each individual, and other forms as 
necessary. 
The Investigator and/or institution is required to prepare and maintain these forms in 
accordance with federal regulations (set forth in the Statement of Investigator Form 
FDA 1572) and to sign, date, and return them to the Sponsor. 
Upon the request of authorized Boston Biomedical or appropriate regulatory agency 
personnel, the Investigator will make available for inspection subject source 


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documents, e.g., records of each subject who participates in this study.  This 
information will be treated as confidential. 
13.7  Record Retention 
Records must be maintained for 25 years: 
If the Investigator leaves the institution where the study was conducted, he/she agrees 
that the records will be retained and will not be destroyed without prior notification of 
Boston Biomedical. 
Boston Biomedical will notify the Investigator when records are no longer required. 
13.8  Subject Confidentiality 
Every effort will be made to keep all subject identities confidential.  All reports and 
communications submitted to the Sponsor will be identified only by the subject’s 
initials and subject number.  The identity of an individual subject may not be 
disclosed in any publication relating to this study. 
In connection with this study, representatives of the US FDA, Health Canada, or other 
regulatory bodies outside of the US and Canada, and representatives of the local IRB 
may, in certain circumstances, review study source documentation including subject 
medical records. 
13.9  Monitoring 
In accordance with good clinical practices, the study will be monitored by Sponsor 
representatives.  These representatives will have access to and will review source 
documents relating to this study, including subject medical records. 
The status of drug storage, dispensing, and accountability will also be assessed during 
periodic visits. 
At any time, each site may be audited either by Boston Biomedical personnel, or by a 
contractor acting on behalf of Boston Biomedical, or by a regulatory agency such as 
the FDA or Health Canada. 
13.10 Case Report Form (CRF) Completion 
A set of CRFs will be provided for each study subject.  All forms must be filled out in 
non-erasable ink or typed.  The Investigator will sign and date each CRF as indicated.  
Correction of data on a CRF will be made by crossing out the incorrect data in a 
manner that leaves the previous entry legible and writing the correct information next 
to the crossed out entry.  “White-out” and erasures are not permitted.  Each correction 
must be initialed and dated by the individual making the correction.  After the CRFs 
have been collected by Boston Biomedical, all corrections will be made via a query 
resolution form, and no further corrections should be made on the site’s copy of the 
CRF. 


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If a web-based Electronic Data Capture (EDC) system is used instead of paper CRFs, 
the details for accessing the EDC system and completing the on-line Case Report 
Forms will be provided separately. 
13.11 Final Site Report 
The Principal Investigator or associate must notify the IRB when the study is closed 
and provide a final report to the IRB within 90 days of the last subject’s completion 
of the study.  A copy of this final report must also be provided to Boston Biomedical. 
13.12 Final Study Report 
At the conclusion of the study, after the data are analyzed, Boston Biomedical will 
prepare a final study report.  A copy of this report will be provided to the Principal 
Investigator at each center. 
The preparation of the final study report may be delegated to a contract research 
organization. 
13.13 Use of Information 
All personal information pertaining to subjects in this study and in any subsequent 
reports will be kept confidential.  Subjects will be identified only by their initials and 
by a subject number.  It is the responsibility of the Investigator to keep a subject 
listing for cross-referencing. 
The Investigator understands that the information developed in the clinical study will 
be used by Boston Biomedical in connection with the development of the study drug.  
This information may be disclosed to other clinical investigators, the FDA, Health 
Canada, and other government agencies. 
All information disclosed to the Investigator(s) by Boston Biomedical for the purpose 
of having the Investigator(s) conduct the clinical trial described in this protocol or 
generated by the Investigator(s) as results in the clinical trial shall be treated by the 
Investigator(s) as strictly confidential.  The Investigator(s) shall not use such 
information other than for the purpose of conducting the clinical trial and may not 
disclose such information to others, except when such disclosure is to colleagues 
and/or employees who reasonably require the information to assist in carrying out the 
clinical trial and who are bound by like obligations of confidentiality.  
Notwithstanding, the Investigator(s) may use or disclose to others any information 
which: (i) was known to the Investigator(s) prior to the date of its disclosure, (ii) is 
now, or becomes in the future, publicly available; or (iii) is lawfully disclosed to the 
Investigator(s) on a non-confidential basis by a third party who is not obligated to 
Boston Biomedical or any other party to retain such information in confidence. 


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13.14  Publication 
Boston Biomedical acknowledges that the Investigator(s) have certain professional 
responsibilities to report to the scientific community on findings in clinical 
investigations they conduct.  The Principal Investigator shall have the right to publish 
the results of research performed under this protocol, provided such publication does 
not disclose any Confidential Information or trade secrets of Boston Biomedical 
(other than the Clinical Data). 
If the Study is conducted as part of a multi-center protocol, the 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 Boston 
Biomedical.
The Principal Investigator agrees to, prior to submitting a manuscript, abstract, or any 
other written or oral presentation describing the Data for publication or presentation, 
forward to Boston Biomedical a copy of the item to be submitted for publication or 
presentation no less than 45 days prior to its submission.  Upon reasonable request by 
Boston Biomedical within 30 days of receipt, the Principal Investigator agrees to 
withhold such publication an additional 30 days to permit the preparation and filing of 
related patent applications.  In addition, Boston Biomedical shall have the right to 
require the Principal Investigator to delete from any publication or presentation any 
Confidential Information (other than the Clinical Data) of Boston Biomedical’s and to 
require that any publication or presentation concerning the Study acknowledge the 
Sponsor’s support.
13.15 Research Outside the Terms of this Protocol 
Boston Biomedical has a legal responsibility to report fully to the regulatory 
authorities all the results of administration of its investigational drugs. 
No investigative procedures other than those described in this protocol shall be 
undertaken on subjects enrolled in this study (unless required for the care of the 
subject), without the agreement of the IRB/Ethics Committee and Boston Biomedical.  
The nature and results of any such procedures must be recorded and reported by a 
method agreed between Boston Biomedical and the Investigator.  The consent of the 
subjects must be obtained before any such procedures are undertaken. 
The investigative drug provided to the Investigator for use under this protocol may 
not be used for any other purpose, including another study, compassionate use, or 
personal use. 


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APPENDIX A:  SCHEDULE OF ASSESSMENTS (ARM A) 
Procedure
Baseline
BBI608 
Monotherapy 
Run-in
Clinical Recovery From Surgery
Combination 
Cycle 
Additional 
Cycles
End of Study Visit
Timing (+/- 3
days,unless 
otherwise noted)
Up to 10 
days 
prior to 
first 
dose 
Day 
1
Day 8 
(Surgery)
Day 
1
Day 
5
Day
8
Day 
15
Day
22
Day 1
30 days from last 
BBI608 dose
Written informed 
consent1
X
Medical history
X
Physical 
examination
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
ECOG 
performance status 
score
X
X
X
X
X
X
X
Serum pregnancy 
test
X
X
X
X
Hematology2
X
X
X
X
X
X
X
X
Biochemistry2
X
X
X
X
X
X
X
X
Urinalysis2
X
X
X
X
X
X
X
X
12-Lead 
electrocardiogram
X
X
X
Tumor Resection3
X
Pharmacokinetics4
X
X
Tumor 
Assessment5,6,7,8
X5
X8
every 8 weeks from Cycle 
1 Day 1
X
Concomitant 
medications
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X9
Dispense TMZ10
X
X
Dispense BBI608
X
X
X
1. Written informed consent may be obtained up to 1 month prior to first dose of BBI608  
2. See Section 6.3  These test must be obtained at Day 1,8,15 and 22 of Cycle 1 and Cycle 2 


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3. Resected tumor tissue will be collected for pharmacodynamics and pharmacokinetic evaluations (see Sections 6.4, 6.5 and 6.6.).  Blood samples will be collected at the time of 
surgery for pharmacokinetic evaluation. Archival FFPE tumor tissue will be collected for all patients. 
4. Pharmacokinetics on day 1 and 5 of cycle 1 will only be performed on patients in the Phase Ib/DLT assessment cohorts 
5. Including tumor measurements, following RANO criteria  
6. At the end of cycle 2 (+/-7 days) of combination therapy and every 8 weeks thereafter (+/-7 days), assessments should be made utilizing the same imaging method as baseline 
and preferably the same imaging machine.  
7. MRI scan performed within 28 days of the first scheduled dose of BBI608 can be used for baseline assessment  
8. MRI scan will be performed within 48-72 hours of surgery in Arm A patients as a baseline scan for the purposes of tumor response assessment. 
9. Patients will be followed until resolution of any drug-related AE or SAE occurring during the study or within 30 days of last BBI608 administration. 
10. TMZ will be administered from day 1 to 5 of every 28 day cycle. 


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APPENDIX B:  SCHEDULE OF ASSESSMENTS (ARM B) 
Procedure
Baseline
Combination Cycle 
Additional 
Cycles
End of Study Visit
Timing (+/- 2 days,unless otherwise 
noted)
Up to 10 days 
prior to first dose 
Day 1
Day 5
Day 8
Day 15
Day 22
Day 1
30 days from last 
BBI608 dose
Written informed consent1
X
Medical history
X
Physical examination
X
X9
X
X
Vital signs
X
X
X
X
X
X
ECOG performance status score
X
X9
X
X
X
X
Serum pregnancy test
X
X
X
Hematology2
X
X9
x
X
x
X
X
Biochemistry2
X
X9
x
X
x
X
X
Urinalysis2
X
X9
x
X
x
X
X
12-Lead electrocardiogram
X
X
X
Pharmacokinetics3
X
X
Tumor Assessment4,5,6
X3
every 8 weeks from Cycle 1 Day 1
X
Concomitant medications
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X7
Dispense TMZ8
X
X
Dispense BBI608
X
X
1. Written informed consent may be obtained up to 1 month prior to first dose of BBI608  
2. See Section 6.3 These test must be obtained at Day 1, 8, 15 and 22 of Cycle 1 and Cycle 2 
3. Pharmacokinetics on day 1 and 5 of cycle 1 will only be performed on patients in the Phase Ib/DLT assessment cohorts 
4. Including tumor measurements, following RANO criteria  
5. At the end of cycle 2 (+/7 days) of combination therapy and every 8 weeks thereafter (+/-7 days), assessments should be made utilizing the same imaging method as baseline 
and preferably the same imaging machine.  
6. MRI scan performed within 28 days of the first scheduled dose of BBI608 can be used for baseline assessment.
7. Patients will be followed until resolution of any drug-related AE or SAE occurring during the study or within 30 days of last BBI608 administration. 
8. TMZ will be administered from day 1 to 5 of every 28 day cycle. 
9. Performed only if the baseline assessments are done prior to 10 days of Cycle 1 Day 1.


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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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SPONSOR SIGNATURE 
Study Title:
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Temozolomide for Adult Patients with Recurrent 
or Progressed Glioblastoma
Study Number:
BBI608-201GBM
This clinical study protocol is subject to critical review and has been approved by the 
Sponsor.  The following personnel contributed to writing and/or approving this protocol: 
Signed: ____________________Date: _____________________ 
Chiang J. Li, MD FACP 
Chief Medical Officer  
Boston Biomedical, Inc.  


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INVESTIGATOR’S SIGNATURE 
Study Title:
A Phase Ib/II Clinical Study of BBI608 in Combination 
with Temozolomide for Adult Patients with Recurrent 
or Progressed Glioblastoma
Study Number:
BBI608-201GBM
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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