Conditions: Malignant Pleural Mesothelioma Non-Small Cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
This is an open-label, multicenter, phase 1/2 study of BBI608 in combination with pemetrexed and cisplatin chemotherapy as a 1st line treatment for Malignant Pleural Mesothelioma (MPM).

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: BBI608 intervention 2: Pemetrexed intervention 3: Cisplatin
Intervention descriptions: intervention 1: 480 mg orally twice daily (960 mg total daily dose) intervention 2: 500 mg/m2 I.V. infusion on Day 1 of each treatment cycle (except for cycle 1, in which Pemetrexed will be given on Day 3). intervention 3: 75 mg/m2 I.V. infusion on Day 1 of each treatment cycle (except for Cycle 1, in which Cisplatin will be given on Day 3).

Protocol document:
Prot_000.pdf: 
Official title: A Phase I/II Clinical Study of BBI608 in Combination With Pemetrexed and Cisplatin 
in Adult Patients With Malignant Pleural Mesothelioma 
NCT number: NCT02347917 
Document date: 5 Jan 2018 


Protocol D8807005, Version 3.02 
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BBI608 
Protocol 
Phase 1/2 study of BBI608 combined with pemetrexed plus cisplatin  
in patients with malignant pleural mesothelioma 
 
 
 
 
 
 
 
Version 3.02 
5 Jan 2018 
 
 
 
 
Sumitomo Dainippon Pharma Co., Ltd. 
1-31-1 Kyobashi, Chuo-ku, Tokyo 
 


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Confidential Information 
 
This protocol and the data gathered during the conduct of this study contain information that is 
proprietary to Sumitomo Dainippon Pharma Co., Ltd. This information is being provided to you for 
the purpose of conducting a clinical study for Sumitomo Dainippon Pharma Co., Ltd. You may 
disclose the contents of this protocol to the investigators and clinical research coordinators under 
your supervision and to your Institutional Review Board for the above purpose. You may not 
disclose the contents of this protocol to any other parties, unless such disclosure is required by 
government regulations or laws, without the prior written permission of Sumitomo Dainippon 
Pharma Co., Ltd. 
 
Any supplemental information (eg, a protocol amendment) that may be added to this document is 
also proprietary to Sumitomo Dainippon Pharma Co., Ltd., and should be handled consistently with 
that stated above. 








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- Hemoglobin (Hb) ≥ 9.0 g/dL (without blood transfusion within the preceding 14 days)  
- Neutrophils ≥ 1500/μL 
- Platelets ≥ 100,000/μL 
- AST and ALT ≤ 2.5-fold the upper limit of the normal range of the laboratory (ULN), or 
≤ 5-fold ULN within 14 days before enrollment for patients with any liver metastasis  
- Total bilirubin ≤ 1.5-fold ULN 
- Creatinine clearance (estimated value)Note) ≥ 60 mL/min 
Note) Creatinine clearance will be calculated using the Cockcroft-Gault formula shown below:  
 Estimated creatinine clearance = (140-age) × body weight / (72 × serum creatinine) (× 0.85 for females)  
• 
Life expectancy ≥ 3 months 
• 
Women of childbearing potential must have a negative pregnancy test (urine) at screening. 
 
<Phase 2 part: Patients with MPM> 
Inclusion Criteria  
• 
Histologically confirmed diagnosis of MPM 
• 
Treatment naïve and not indicated for surgery  
• 
Evaluable according to the mRECIST 
• 
Age ≥ 20 years at the time of consent  
• 
Provided written voluntary consent in person to participate in this study and tumor tissue 
sampling after fully receiving and understanding information about the study, including 
study objectives, contents, expected pharmacological effects and foreseeable risks  
• 
Agree to use appropriate contraception from the time of consent until 30 days after the last 
dose of the study drug to avoid pregnancy of the female participant or a female partner of 
the male participant  
• 
ECOG PS 0 or 1 within 14 days before enrollment  
• 
Adequate major organ functions meeting the following criteria based on latest laboratory 
tests within 14 days before enrollment  
• 
Hemoglobin (Hb) ≥ 9.0 g/dL (without blood transfusion within the preceding 14 days)   
- Neutrophils ≥ 1500/μL 
- Platelets ≥ 100,000/μL 
- AST and ALT ≤ 2.5-fold ULN, or ≤ 5-fold ULN within 14 days before enrollment for 
patients with any liver metastasis  
- Total bilirubin ≤ 1.5-fold ULN  
- Creatinine clearance (estimated value)Note) ≥ 60 mL/min 
Note) Creatinine clearance will be calculated using the Cockcroft-Gault formula shown below:  
Estimated creatinine clearance = (140-age) × body weight / (72 × serum creatinine) (× 0.85 for females)  
• 
Life expectancy ≥ 3 months 
• 
Women of childbearing potential must have a negative pregnancy test (urine) at screening 
 
<For both Phase 1 and 2 parts> 
Exclusion Criteria:  
• 
Have received any of the following treatments “a)” to “c)” for the primary disease before 
enrollment in this study 
a) Chemotherapy and surgical therapy (MPM only. excluding surgical biopsy) 
b) Radiotherapy, with the exception of palliative irradiation for pain control or symptomatic 
relief performed within 14 days before enrollment  
c) Hormonal therapy, immunotherapy, thermotherapy, surgical therapy (NSCLC only. 
excluding surgical biopsy), or other antitumor treatments performed within 21 days before 
enrollment 


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• 
Any brain metastasis requiring treatment or symptomatic 
• 
Presence of multiple active cancers at registration (i.e., synchronous multiple primary 
cancers, or metachronous multiple primary cancers with a disease-free period of ≤5 years, 
with the exception of curatively treated local carcinoma in situ or submucosal carcinoma)  
• 
Presence of Crohn’s disease or ulcerative colitis, or have a history of extensive resection of 
the small intestine 
• 
Presence of significant 12-lead ECG abnormality within 28 days before enrollment 
• 
History of myocardial infarction within 6 months before enrollment  
• 
Current use of antiarrhythmic medication, with the exception of anticoagulant therapy for 
atrial fibrillation  
• 
Presence of any uncontrolled concurrent disease (e.g., active infection, unstable angina, 
significant respiratory disease)  
• 
Known hypersensitivity to Pem, CDDP or other drugs containing platinum 
• 
Pregnant or possibly pregnant women, or women planning to breastfeed between the first 
dose of BBI608 to 30 days after the last dose of BBI608 
• 
Have received any other investigational drug within 28 days before enrollment in this study  
• 
Possible inability to swallow BBI608 for certain reasons such as dysphagia 
• 
Previously received BBI608 
• 
Inappropriate for participation in the study for other reasons in the opinion of the 
investigator or subinvestigator 
Protocol Treatment, Study Drugs, Dosage and Mode of Administration:  
Protocol treatment is defined as BBI608 in combination with Pem plus CDDP.  
• 
BBI608 
BBI608 will be orally administered at a dose of 480 mg twice daily (morning and evening) (daily 
dose, 960 mg). Each dose will be taken at either 1 hour before or 2 hours after a meal, with 
dosing intervals of approximately 12 hours. On Day 1 of Phase 1 part, however, only the morning 
dose will be administered.  
• 
Pemetrexed (Pem) 
Pem, for which a marketed product will be used, will be intravenously administered at 500 
mg/m2 by drip infusion over 10 minutes on Day 1 of each treatment cycle (except for Cycle 1, in 
which Pem will be given on Day 3). Meanwhile, Pem will be administered with an interval of at 
least 4 hours after BBI608 dosing in Cycle 1 of phase 1 part only. Premeditation with folic acid 
and vitamin B12 should be given to reduce occurrence of serious adverse drug reactions, with 
reference to the package insert for Pem.  
• 
Cisplatin (CDDP) 
CDDP, as a marketed product, will be intravenously administered at 75 mg/m2 by drip infusion 
over ≥2 hours. Each infusion of CDDP will start at 30 to 50 minutes after a dose of Pem. To 
reduce nephrotoxicity of CDDP, fluid infusion, diuretic therapy, and other treatments should be 
given, with reference to the package insert for CDDP.  
Duration of Treatment:  
Each cycle consists of 21 days (with the exception of Cycle 1 which consists of 23 days). No 
restriction is set on the number of cycles.  
In Cycle 1, Day 1 will be the first day of BBI608 administration. From Cycle 2 onward, Day 1 will 
be the day of administration of Pem and CDDP (or the day of administration of Pem after 
discontinuation of CDDP in NSCLC patients in Phase 1 part).  
Protocol treatment will be continued in the following manner:  
- Protocol treatment with the three drugs should be repeated as long as possible; no restriction is 
set on the number of cycles.  
- If an adverse event associated with either Pem or CDDP is judged to require treatment 
discontinuation, both Pem and CDDP should be discontinued, while BBI608 will be 


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continued as long as possible. For NSCLC patients, however, only CDDP may be 
discontinued at the discretion of the investigator or subinvestigator.  
- Even after assessment of PD according to the RECIST 1.1 or mRECIST, administration of 
BBI608 may be continued until the treatment is no longer clinically beneficial to the patient in 
the opinion of the investigator or subinvestigator for certain reasons such as intolerable adverse 
events or further progression of the primary disease.  
Reference Treatment, Dosage and Mode of Administration: Not applicable 
Concomitant Medications and Therapies: 
<Prohibited concomitant medications and therapies> 
• 
Anticancer chemotherapy (other than Pem and CDDP as the components of protocol 
treatment), radiotherapy, hormonal therapy, immunotherapy, thermotherapy, surgical 
therapy, or other therapies for cancer 
• 
Other investigational drugs, post-marketing clinical study drugs, or drugs unapproved in 
Japan 
• 
Therapies with immunosuppressive effects (e.g., systemic steroids), with the exception of 
intermittent use for antiemesis, use at a less-than-immunosuppressive dose for malaise or 
appetite loss, or prophylactic use after onset of rash. 
• 
Until the end of the DLT evaluation period in Phase 1 part, prophylactic use of granulocyte 
colony stimulating factor (G-CSF) products 
Study Endpoints:  
Phase 1 part 
<Safety endpoints> 
Adverse events and adverse drug reactions, DLT, vital signs, body weight, laboratory test values, 
12-lead ECG, chest X-ray, and ECOG PS 
<Efficacy endpoints> 
Tumor response, progression-free survival (PFS), overall survival (OS), respiratory function tests 
(vital capacity [VC], forced vital capacity [FVC], forced expiratory volume in the first second 
[FEV1]) 
<Pharmacokinetic endpoints> 
BBI608 pharmacokinetic parameters of the following: 
Maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), area under the 
plasma concentration-time curve from time zero to 12 hours (AUC0-12), area under the plasma 
concentration-time curve from time zero to 24 hours (AUC0-24), area under the plasma 
concentration-time curve from time zero to infinity (AUC0-∞), time to maximum plasma 
concentration (tmax), terminal elimination rate constant (λz), terminal elimination half-life (t1/2), 
mean residence time (MRT) 
 
Phase 2 part 
<Efficacy endpoints> 
PFS, OS, tumor response (response rate [RR], disease control rate [DCR]), respiratory function 
tests (VC, FVC, FEV1) 
<Safety endpoints> 
Adverse events and adverse drug reactions, vital signs, body weight, laboratory test values, 12-lead 
ECG, chest X-ray, ECOG PS 
<Other endpoints> 
Biomarkers (β-catenin, phospho-STAT3 (p-STAT3), merlin) 
Statistical Methods: 
<Analysis sets> 


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• 
Safety and efficacy: A set of all subjects who received the investigational drug. 
• 
DLT evaluation: A set of subjects who received the investigational drug in Phase 1 part, who 
had a ≥ 80% BBI608 treatment compliance rate during the DLT evaluation period, and who 
experienced DLT during the DLT evaluation period 
• 
Pharmacokinetics: A set of subjects who received BBI608 with the post-dose plasma 
BBI608 concentration data available for at least one time point. 
 
<Efficacy analytical items> 
• 
Tumor response: Best overall response 
• 
PFS: Time from BBI608 administration to documented PD (as assessed according to the 
mRECIST or RECIST 1.1) or death, whichever is earlier  
• 
OS: Time from BBI608 administration to death from any cause 
• 
Respiratory function tests: VC, FVC, FEV1 






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m) 
Cycle 1 treatment is given for 23 days; data up to Day 24 examination will be regarded Cycle 1 data.  
n) 
Performed before BBI608 administration.  
o) 
If Day 1 of Cycle 2 is the same day as Day 24 of Cycle 1, the procedures scheduled for Day 1 of Cycle 2 will be omitted with the exception of “BBI608 administration, 
compliance” and “Pem and CDDP administration, compliance.” 
p) 
If this was performed on the previous day of Pem and CDDP administration, that result can be used. Meanwhile, if the administration of Pem and CDDP was discontinued, this 
will be performed from the next day of Pem and CDDP administration in the previous cycle in every 21 days (±7 days).   
q) 
Not required if Pem and CDDP were discontinued.   
r) 
If subsequent treatment is started during the follow-up observation period, these will be performed before subsequent treatment. Available data obtained within 14 days before 
the start of subsequent treatment may be alternatively used.  
s) 
If judged necessary by the sponsor, patient outcome investigation may be continued beyond 1 year after last subject’s treatment start date.  
 


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Table 3  Schedule of Imaging and Respiratory Function Tests in Phase 1 and 2 Parts  
Months 
- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
… 
Weeks 
- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 33 
. 
Imaging 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
● 
 
Respiratory 
function 
tests 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
● 
 
 
 
Requirements for imaging and respiratory function tests are as follows:  
- For screening imaging, available imaging obtained within 14 days before enrollment may be alternatively used if the imaging conditions were in line with the RECIST 1.1 for 
NSCLC patients or the mRECIST for MPM patients.  
- A baseline respiratory function test will be performed from 7 days till right before the first dose of BBI608.  
 
 
- The allowable range for imaging and respiratory function tests is ±1 week. Imaging and respiratory function tests will be performed every 6 weeks from the first dose of BBI608 
(Day 1 of Cycle 1) until Week 30, and then every 9 weeks from Week 31 on. The schedule of imaging and respiratory function tests is based only on Day 1 of Cycle 1, irrespective 
of Day 1 of Cycle 2 or any later cycle. 
- If protocol treatment is discontinued because of imaging-documented worsening, no further imaging and respiratory function tests are required. 
- If protocol treatment is discontinued because of other reason than imaging-documented worsening, imaging and respiratory function tests will be continued according to the test 
schedule even after discontinuation of protocol treatment until worsening is judged by an imaging test. If subsequent treatment is started before the judgment of worsening by an 
imaging test, imaging and respiratory function tests will be performed before subsequent treatment as far as possible, and no further imaging and respiratory function tests is 
required after initiation of subsequent treatment. 
6 weeks 
6 weeks 
6 weeks 
9 weeks 
6 weeks 
6weeks 




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bloodsampling 
dosing 
dosing 
dosing 
BBI608 PK blood sampling 
● 
 
● 
● 
● 
● 
● 
● 
● 
 
a) On Days 1, 3 and 23 of Cycle 1, the date and time of meal intake should be recorded. On Days 1 to 3, 22 and 23 of Cycle 1, the date and time of medication should be recorded. 
From Day 1 to Day 23 of Cycle 1, the number of capsules taken should be recorded.  
b) On Day 3 of Cycle 1, the start time and end time of each dosing of Pem and CDDP, and of each fluid infusion before and after CDDP administration, should be recorded. 
c) One blood sample will be collected just before or after Pem dose, or just before CDDP dose.   
d) Within 5 minutes after the end of intravenous drip infusion of the drug.  
 




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e) 
Written consent must be obtained before screening examination.  
f) 
Available data obtained within 28 days before enrollment may be alternatively used.  
g) 
Performed within 3 days before the start of study treatment.  
h) 
If screening examination was performed within 7 days before the start of BBI608 administration, the results 
from screening examination may be used as baseline data. If screening examination was performed ≥ 7 days 
before the start of BBI608 administration, baseline data should be newly obtained before the start of BBI608 
administration.   
i) 
Performed after BBI608 administration.  
j) 
If this was performed on the previous day of Pem and CDDP administration, that result can be used. 
Meanwhile, if the administration of Pem and CDDP was discontinued, this will be performed from the next 
day of Pem and CDDP administration in the previous cycle in every 21 days (±7 days). 
k) 
Not required if Pem and CDDP were discontinued.  
l) 
If subsequent treatment is started during the follow-up observation period, these will be performed before 
subsequent treatment. Available data obtained within 14 days before the start of subsequent treatment may be 
alternatively used.  
m) 
If judged necessary by the sponsor, patient outcome investigation may be continued beyond 1 year after last 
subject’s treatment start date.   


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2. TABLE OF CONTENTS 
1. SYNOPSIS ...................................................................................................................................... 4 
2. TABLE OF CONTENTS ............................................................................................................... 18 
3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................... 23 
4. INTRODUCTION ......................................................................................................................... 25 
4.1 Background ............................................................................................................................ 25 
4.2 Study Conduct Rationale ........................................................................................................ 26 
 Nonclinical Studies ......................................................................................................... 26 
 Clinical Studies ............................................................................................................... 26 
 Multinational Clinical Studies ......................................................................................... 29 
4.3 Present Investigational Plan ................................................................................................... 29 
5. STUDY OBJECTIVES ................................................................................................................. 30 
5.1 Phase 1 Part ............................................................................................................................ 30 
 Primary Objective ........................................................................................................... 30 
 Secondary Objective ....................................................................................................... 30 
5.2 Phase 2 Part ............................................................................................................................ 30 
 Primary Objectives .......................................................................................................... 30 
 Secondary Objective ....................................................................................................... 30 
6. STUDY ENDPOINTS ................................................................................................................... 30 
6.1 Phase 1 Part ............................................................................................................................ 30 
 Safety Endpoints ............................................................................................................. 30 
 Efficacy Endpoints .......................................................................................................... 30 
 Pharmacokinetic Endpoints ............................................................................................. 30 
6.2 Phase 2 Part ............................................................................................................................ 31 
 Efficacy Endpoints .......................................................................................................... 31 
 Safety Endpoints ............................................................................................................. 31 
 Other Endpoints .............................................................................................................. 31 
7. INVESTIGATIONAL PLAN ........................................................................................................ 31 
7.1 Overall Study Design ............................................................................................................. 31 
 Phase 1 Part ..................................................................................................................... 32 
 Phase 2 Part ..................................................................................................................... 35 
7.2 Rationale................................................................................................................................. 36 
 Rationale for the Study Design ....................................................................................... 36 
 Rationale for the Dosages ............................................................................................... 36 
 Rationale for the Study Population ................................................................................. 37 


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 Rationale for the Endpoints ............................................................................................. 38 
7.3 Planned Study Period ............................................................................................................. 38 
8. SELECTION OF SUBJECTS ....................................................................................................... 38 
8.1 Inclusion Criteria .................................................................................................................... 38 
 Phase 1 Part ..................................................................................................................... 38 
 Phase 2 Part ..................................................................................................................... 39 
8.2 Exclusion Criteria ................................................................................................................... 40 
9. STUDY DRUG MATERIALS AND MANAGEMENT ............................................................... 41 
9.1 Description of Investigational Drug ....................................................................................... 41 
9.2 Investigational Drug Packaging and Labeling ....................................................................... 41 
 Package Description ........................................................................................................ 41 
 Labeling Description ....................................................................................................... 41 
9.3 Investigational Drug Storage .................................................................................................. 41 
9.4 Dispensing of Investigational Drug ........................................................................................ 41 
9.5 Investigational Drug Accountability....................................................................................... 41 
9.6 Investigational Drug Handling and Disposal ......................................................................... 42 
10. TREATMENT OF SUBJECTS ..................................................................................................... 42 
10.1 Study Medication ................................................................................................................... 44 
10.2 Criteria for Protocol Treatment Modification ......................................................................... 45 
10.3 Treatment Compliance ........................................................................................................... 49 
10.4 Treatment Period, Follow-Up Observation Period, Patient Outcome Investigation and 
Subsequent Treatment ............................................................................................................ 49 
10.5 Definition of DLT and Enrollment of Additional Subjects (Phase 1 Part) ............................. 50 
 Definition of DLT............................................................................................................ 50 
 DLT Evaluation Period and Subjects Evaluated for DLT................................................ 51 
 Enrollment of Additional Subjects .................................................................................. 51 
10.6 Concomitant Medications and Therapies ............................................................................... 51 
 Prohibited Concomitant Medications and Prohibited Concomitant Therapies ............... 52 
 Restricted Concomitant Medications .............................................................................. 52 
 Permitted Concomitant Medications ............................................................................... 53 
10.7 Restrictions ............................................................................................................................. 54 
10.8 Contraception Requirements .................................................................................................. 54 
10.9 Treatment Assignment and Blinding ...................................................................................... 54 
11. STUDY ASSESSMENTS ............................................................................................................. 54 
11.1 Demographic and Baseline Characteristics ............................................................................ 55 
Phase 1 Part ..................................................................................................................... 55 


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Phase 2 Part ..................................................................................................................... 55 
11.2 Efficacy Assessments ............................................................................................................. 56 
 Tumor Response .............................................................................................................. 56 
Patient Outcome .............................................................................................................. 58 
Respiratory Function Tests .............................................................................................. 59 
11.3 Safety Assessments ................................................................................................................ 59 
Adverse Events ............................................................................................................... 59 
DLT (Phase 1 Part) .......................................................................................................... 59 
Clinical Laboratory Tests ................................................................................................ 59 
 Vital Signs and Body Weight .......................................................................................... 59 
Chest X-ray ..................................................................................................................... 59 
 12-lead ECG .................................................................................................................... 60 
ECOG PS ........................................................................................................................ 60 
11.4 Pharmacokinetic Assessments (Phase 1 Part) ......................................................................... 60 
 Plasma Drug Concentrations ........................................................................................... 60 
 Exploratory Analysis of Metabolites in Plasma .............................................................. 61 
11.5 Biomarkers ............................................................................................................................. 61 
12. SAFETY REPORTING ................................................................................................................. 62 
12.1 Definitions .............................................................................................................................. 62 
 Adverse Events ............................................................................................................... 62 
 Serious Adverse Events ................................................................................................... 63 
 Adverse Drug Reactions ................................................................................................. 64 
12.2 Abnormal Findings ................................................................................................................. 64 
12.3 Collection and Recording of Adverse Events ......................................................................... 64 
12.4 Immediately Reportable Events ............................................................................................. 67 
 Serious Adverse Events ................................................................................................... 67 
 Pregnancy ........................................................................................................................ 68 
12.5 Data and Safety Monitoring Board......................................................................................... 69 
13. TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF STUDY DRUG .... 69 
13.1 Criteria for Study Drug Discontinuation ................................................................................ 69 
13.2 Criteria for Subject Withdrawal from Patient Outcome Investigation ................................... 70 
13.3 Clinical Assessments After Protocol Treatment Discontinuation ........................................... 70 
14. STUDY TERMINATION .............................................................................................................. 70 
15. STATISTICS .................................................................................................................................. 71 
15.1 Sample Size Determination .................................................................................................... 71 
15.2 Analysis Populations .............................................................................................................. 72 


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 Safety Analysis Population ............................................................................................. 72 
 DLT Evaluation Population ............................................................................................. 72 
 Pharmacokinetics Population .......................................................................................... 72 
 Efficacy Analysis Population (Modified Intention-to-Treat Population) ........................ 72 
15.3 Data Analysis.......................................................................................................................... 72 
 Subject Disposition ......................................................................................................... 72 
 Drug Exposure and Compliance ..................................................................................... 72 
 Important Protocol Deviations ........................................................................................ 73 
 Demographic and Other Baseline Characteristics ........................................................... 73 
 Efficacy Analysis ............................................................................................................ 73 
 Safety Analysis ................................................................................................................ 74 
 Pharmacokinetic Analysis ............................................................................................... 76 
 Interim Analysis .............................................................................................................. 76 
 Handling of Data ............................................................................................................. 76 
16. PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL, DATA COLLECTION, 
DATA MANAGEMENT, AND QUALITY ASSURANCE .......................................................... 77 
16.1 Data Collection/Electronic Data Capture (EDC).................................................................... 77 
16.2 Study Monitoring ................................................................................................................... 78 
16.3 Audits ..................................................................................................................................... 78 
16.4 Study Documentation ............................................................................................................. 78 
16.5 Clinical Laboratory Certification and Normal Values ............................................................ 78 
17. ETHICAL AND REGULATORY OBLIGATIONS ...................................................................... 78 
17.1 Ethical Conduct of the Study and GCP Compliance .............................................................. 78 
17.2 Institutional Review Board ..................................................................................................... 79 
17.3 Informed Consent ................................................................................................................... 79 
17.4 Subject Privacy ....................................................................................................................... 80 
17.5 Protocol Amendments and Emergency Deviations ................................................................ 81 
17.6 Records Retention .................................................................................................................. 81 
17.7 Inspection of Records by Regulatory Agencies ...................................................................... 82 
17.8 Publication Policy .................................................................................................................. 82 
17.9 Compensation ......................................................................................................................... 82 
17.10 
Payment of Transportation Fees and Other Expenses Associated with Participation 
in the Study to Reduce Financial Burdens on Subjects .......................................................... 82 
18. REFERENCES .............................................................................................................................. 83 
19. APPENDIX ................................................................................................................................... 84 


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List of Tables 
Table 1 Emergency Contact Information ........................................................................................ 3 
Table 2  Schedule of Assessments in Phase 1 Part ........................................................................ 10 
Table 3  Schedule of Imaging in Phase 1 and 2 Parts ................................................................... 13 
Table 4  Schedule of Pharmacokinetic Assessment in Phase 1 part .............................................. 14 
Table 5  Schedule of Assessments in Phase 2 Part ........................................................................ 16 
Table 6  List of Abbreviations ....................................................................................................... 23 
Table 7   BBI608 Dosage Modification Table .............................................................................. 46 
Table 8  Recommended Supportive Therapies for Common Adverse Events with BBI608 
(unless contraindicated) ................................................................................................... 47 
Table 9  Criteria for Starting Pem and CDDP Administration ...................................................... 47 
Table 10  Pem and CDDP Dose Modification for Hematotoxicity ............................................... 48 
Table 11  Pem and CDDP Dose Modification for Non-hematotoxicity (Other Than 
Neurotoxicity) .................................................................................................................. 49 
Table 12  Pem and CDDP Dose Modification for Neurotoxicity .................................................. 49 
Table 13  Pem and CDDP Dose Modification for Renal Impairment ........................................... 49 
 
 
List of Figures 
Figure 1  Flowchart of Enrollment of Additional Subjects ........................................................... 33 
Figure 2  Flowchart of Study Procedures in Individual Subjects (Phase 1 Part) .......................... 33 
Figure 3  Schedule of BBI608, Pem and CDDP Co-administration in a Day ............................... 34 
Figure 4  Flowchart of Study Procedures in Individual Subjects (Phase 2 Part) .......................... 35 
Figure 5  Subject Enrollment Procedures ..................................................................................... 44 
 
 
 
 
 


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3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The abbreviations used in this protocol are shown in Table 6.  
 
Table 6  List of Abbreviations 
Abbreviation 
Full Form  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
AUC0-12 
Area under the concentration-time curve from time zero to 12 
AUC0-24 
Area under the concentration-time curve from time zero to 24 
AUC0-∞ 
Area under the concentration-time curve from time zero to infinity 
CDDP 
Cisplatin 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CR 
Complete response 
CSC 
Cancer stem cell 
CT 
Computed tomography 
CTCAE 
v4.0-JCOG 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0-Japanese translation 
by Japan Clinical Oncology Group 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DRM 
Data review meeting 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
FEV1 
Forced expiratory volume in 1st second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
Hb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HMG-CoA 
3-Hydroxy-3-methylglutaryl-coenzyme A 
IC50 
50% inhibitory concentration 
ICH 
International Conference on Harmonization 
IL-6 
Interleukin-6 
IPDs 
Important protocol deviations 
IRB 
Institutional review board 
ITT 
Intention-to-Treat 
λz 
Terminal elimination rate constant 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MPM 
Malignant pleural mesothelioma 
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
MRI 
Magnetic resonance imaging 
MRT 
Mean residence time 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
NSCLC 
Non-small cell lung cancer 
NE 
Not evaluable 
Non-CR/Non-PD 
Non-complete response /Non-progressive disease 
OS 
Overall survival 
PD 
Progressive disease 
Pem 
Pemetrexed 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
PS 
Performance status 
p-STAT3 
Phospho-signal transducer and activator of transcription 3 
PT 
Preferred term 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RD 
Recommended dose 
RP2D 
Recommended phase 2 dose 
RR 
Response rate 
STAT3 
Signal transducer and activator of transcription 3 
SD 
Stable disease 
SOC 
System organ class 
tmax 
Time to maximum observed concentration 
t1/2 
Terminal elimination half-life 
VC 
Vital capacity 
 


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4. INTRODUCTION 
4.1 Background 
Malignant mesothelioma is difficult to diagnose and treat, and has very poor prognosis. Although it 
is a rare disease, the reported annual deaths from malignant mesothelioma in Japan were 710 in 
2000, 911 in 2005, and 1410 in 2013,1) showing a rapid increase in recent years. Malignant 
mesothelioma develops most commonly in the pleura, with malignant pleural mesothelioma 
(MPM) accounting for ≥ 90% of all cases of malignant mesothelioma, but also can develop in the 
pericardium, peritoneum, or tunica vaginalis. The most common cause is asbestos.2) Given that the 
latency period from asbestos exposure and development of the disease is 25–30 years or longer, the 
peak prevalence of malignant mesothelioma in Japan is said to occur around 2025–2030.3) 
 
Trimodality therapy (consisting of surgical therapy, radiotherapy and chemotherapy) is 
recommended as first-choice treatment for malignant mesothelioma. Patients not indicated for 
trimodality therapy are treated with chemotherapy alone.4) Currently, the only standard primary 
chemotherapy is the combination use of a folate metabolism inhibitor pemetrexed (Pem) and a 
platinum agent cisplatin (CDDP)5),6), but its therapeutic benefits have been unsatisfactory. Thus, 
new anticancer therapies with better antitumor effects on malignant mesothelioma are needed. 
Second and subsequent lines of treatment have no established evidence. 
 
Recent reports increasingly describe that cancer stem cells (CSC), also called tumor-initiating cells, 
which are the cancer cells that have self-renewal ability, are involved in various cancer types 
including MPM. CSCs are now believed to play a major role in malignant tumor growth, 
recurrence, and metastasis.7)-11) Since CSCs are resistant to medications compared with non-stem 
cancer cells (i.e., cancer cells other than cancer stem cells), the existence of CSCs is recognized as 
the underlying mechanism for refractoriness.8),9) Thus, discovery of an effective method to 
eliminate CSCs is expected to lead a way to the development of curative treatment that can even 
prevent cancer metastasis and recurrence. 
 
Many malignant mesothelioma cells are known to secrete interleukin-6 (IL-6) and IL-6 has been 
described to induce multiplication of malignant mesothelioma cells; thus, inhibition of IL-6 
signaling can inhibit tumor growth.12) In addition, signal transducer and activator of transcription 3 
(STAT3), which is a transcription factor downstream of IL-6, is known to be highly expressed in 
malignant mesothelioma cells.13) Abnormal expression and activation of the STAT3 signal 
transduction pathway are reported in various cancer types,14) with significant correlation between 
its expression status and prognosis for colorectal cancer, gastric cancer, head and neck cancer, 
breast cancer, ovarian cancer.15)-19) Inactivation of the STAT3 signal transduction pathway by gene 
targeting or other methods has shown inhibition of cancer growth, survival, and metastasis.14)  


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BBI608 is a novel, small-molecule compound targeting CSCs being developed for anticancer 
treatment. BBI608 inhibits the STAT3 signal transduction pathway, and therefore can inhibit 
self-renewal and survival of CSCs, thus inducing apoptosis of both CSCs and non-stem cancer cells. 
STAT3 is overexpressed in malignant mesothelioma, including MPM. Thus, BBI608 can be a 
useful treatment option for patients with MPM, and therefore the present study was planned.  
 
4.2 Study Conduct Rationale 
 
Nonclinical Studies  
BBI608 showed potent proliferation inhibitory activity against CSCs, but little proliferation 
inhibitory activity against normal hematopoietic stem cells. Various cancer cells with active STAT3 
were sensitive to BBI608, compared with cancer cells with inactive STAT3. BBI608 showed in 
vitro cytotoxic activity against various human cancer cell lines, including lung cancer and MPM. 
Also in vivo studies using xenograft mouse models of human cancers such as colorectal cancer 
showed potent antitumor activity with favorable tolerability. Furthermore, a mouse model of 
metastatic tumors demonstrated potent anti-metastatic activity.  
 
In vitro studies using cytochrome P450 (CYP) isoforms showed that BBI608 had moderate 
inhibitory activity against 1A2, 2D6 and 2C19 (IC50: 0.25, 0.25, and 0.5 μM, respectively) and 
relatively low inhibitory activity against 2C9 and 3A4 (IC50: 2.5 and 5 μM, respectively).  
 
 
Clinical Studies  
4.2.2.1 
Overseas Clinical Studies  
(1) Study 101 
Study 101 was the first-in-human Phase 1 study of BBI608 conducted in the US and Canada from 
. The study objective was to evaluate the safety and pharmacokinetics of BBI608 monotherapy 
using the dose-escalation design in patients with advanced solid tumors, and determine the 
recommended phase 2 dose (RP2D). The efficacy was evaluated in patients with advanced 
colorectal cancer in the RP2D expansion cohort.  
 
BBI608 was well tolerated, and adverse events were mostly mild. Common adverse events were 
grade 1 or 2 transient diarrhea, nausea and vomiting. Grade 3 adverse events were fatigue, transient 
diarrhea, abdominal colic, nausea, anorexia, and hypophosphatemia. The most common adverse 
event was diarrhea. Most events of diarrhea were mild, occurred within the first week of treatment, 
and resolved with treatment after a median duration of 2 days. These events of diarrhea were likely 
osmotic in etiology.  
 


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In terms of tumor response, SD for ≥ 12 weeks was observed in 46% of evaluable patients.  
 
(2) Other clinical studies   
In addition to the above study, the following overseas clinical studies are ongoing:  
- A Phase Ib/II study of BBI608 combined with paclitaxel in adult patients with advanced 
malignancies (Study 201)  
- A Phase II study of BBI608 combined with cetuximab, panitumumab or capecitabine in 
patients with advanced colorectal cancer (Study 224)  
- A Phase Ib study of BBI608 combined with standard chemotherapies in patients with 
advanced gastrointestinal cancer (Study 246)  
 
All adverse events reported from these studies have been essentially consistent with the adverse 
events reported earlier, and no adverse events raised particular issues.  
 
4.2.2.2 
Japanese Clinical Studies   
(1) Study D8801001 
Study D8801001 is an ongoing, phase 1, open-label, uncontrolled study with dose titration using 
the 3 + 3 design in Japanese patients with advanced solid cancers to determine the dose limiting 
toxicity (DLT) and maximum tolerated dose (MTD) of BBI608. BBI608 is administered orally at 
480 mg/day, 960 mg/day or 1440 mg/day in two divided doses (at 12-hour intervals), either 1 hour 
before or 2 hours after a meal.  
 
DLT evaluation was completed for all cohorts by 
. Cohort 1 (480 mg/day) was 
performed in 3 patients with colorectal cancer, and all 3 patients completed the DLT evaluation 
without experiencing any DLT. Cohort 2 (960 mg/day) was performed in 4 patients with colorectal 
cancer, and all 4 patients completed the DLT evaluation period without experiencing any DLT. In 
Cohort 3 (1440 mg/day), 1 of 3 colorectal cancer patients who were administered the drug 
experienced DLT (grade 3 decreased appetite). Therefore, 2 colorectal cancer patients and 1 adrenal 
cancer patient were added to evaluate DLT. One of 3 additional patients experienced a serious 
adverse event (grade 2 acute enteritis, not related to the study drug); thus, the treatment was 
discontinued due to the subject’s intention on Day 6. Accordingly, 1 colorectal cancer patient was 
added and the DLT evaluation period was completed. 3 patients who were applicable to DLT 
evaluation did not experience DLT. 
 
As of 
, adverse drug reactions reported in 2 or more patients were diarrhoea (66.7%, 
8/12 patients) as well as nausea, vomiting, and decreased appetite (25.0% each, 3/12 patients each), 
and gastrointestinal adverse drug reactions have been common. Most adverse drug reactions were 


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grade 1 or 2, and the only grade ≥3 adverse drug reactions were diarrhoea and decreased appetite in 
1 patient in Cohort 3. About half of adverse drug reactions occurred within the first 4 days of 
BBI608 therapy. Compared with common adverse events in non-Japanese patients in overseas 
clinical studies, i.e., grade 1 or 2 transient diarrhoea, nausea, vomiting or other gastrointestinal 
adverse events, adverse events in Japanese patients showed no particular differences. One patient in 
Cohort 2 discontinued treatment during the DLT evaluation period after experiencing adverse 
events of nausea, vomiting, dehydration, worsening of anorexia, delirium, of renal failure, which 
were attributed by the investigator to either progression of the primary disease or opioid use for the 
control of symptoms associated with the primary disease.  
 
Pharmacokinetic data were compared between Japanese patients and non-Japanese patients. 
Although the sample size differed between the two populations, the plasma concentrations in 
Japanese patients were within the range of variation of plasma concentrations in non-Japanese 
patients. Also, the distribution of maximum observed concentration (Cmax) and area under the 
concentration-time curve from time zero to 24 (AUC0-24) indicated no substantial difference in the 
extent of exposure between Japanese patients and non-Japanese patients.  
 
(2) Study D8806004 
Study D8806004 is an ongoing phase 1 study in patients with unresectable/recurrent gastric cancer 
with disease progression after one or more chemotherapy regimens, to determine the safety, 
tolerability and pharmacokinetics of BBI608 combined with paclitaxel (80 mg/m2 intravenously 
three times a week in 4-week cycles). BBI608 is orally administered at a dose of 480 mg twice 
daily (12-hour intervals) (daily dose, 960 mg/day), at either 1 hour before or 2 hours after a meal. 
As of 
, 6 patients received the investigational drug and 1 patient remains on treatment.  
 
In terms of the safety, no DLT occurred in 6 patients assessed for DLT. No serious adverse events 
occurred during the DLT evaluation period. Adverse drug reactions reported in 2 or more patients 
were diarrhoea and anorexia. Almost all adverse drug reactions were grade 1. About half of adverse 
drug reactions occurred within the first 4 days of BBI608 therapy. 
 
Pharmacokinetic data showed profound inter-individual differences, but the time-course of plasma 
BBI608 concentrations did not show major difference between single-dose administration and 
multiple-dose administration in individual cycles. Between patients with total or partial 
gastrectomy and those without gastrectomy, the time-course of plasma BBI608 concentrations did 
not show major difference, either after single-dose administration or multiple-dose administration.  
 


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Multinational Clinical Studies   
A phase 3 multinational, placebo-controlled study (Study CO.23) is ongoing in patients with 
previously treated advanced colorectal cancer. A phase 3, multinational, placebo-controlled, 
double-blind, randomized study of BBI608 combined with paclitaxel (Study 336) is ongoing in 
patients with advanced previously treated gastric or gastro-esophageal junction adenocarcinoma. 
These studies are conducted in multiple countries including Japan. All adverse events reported from 
these studies were essentially consistent with the adverse events reported earlier, and no adverse 
events raised particular issues. For Study CO.23, the protocol-specified sample size was reached, 
and the first interim analysis was performed, revealing that the disease control rate (DCR) did not 
meet the pre-established criteria. Thus, the independent safety data monitoring committee advised 
to discontinue enrollment of new patients and discontinuation of treatment in already enrolled 
patients. Enrollment of new patients was discontinued on 
. Treatment was withdrawn 
in already enrolled approximately 280 patients, including 44 Japanese patients. The primary 
endpoint of overall survival (OS) is to be analyzed.  
 
4.3 Present Investigational Plan
The present study is a phase 1/2, open-label, uncontrolled study. Phase 1 part is conducted in 
patients with malignant pleural mesothelioma (MPM) or non-small cell lung cancer (NSCLC) to 
evaluate the safety, tolerability and pharmacokinetics of BBI608 960 mg/day combined with Pem 
plus CDDP (protocol treatment).  
 
Phase 2 part is conducted in patients with MPM to primarily evaluate the efficacy (based on 
progression-free survival [PFS] as the primary endpoint) and safety of BBI608 combined with Pem 
plus CDDP, and secondarily explore biomarkers related to the efficacy.  
 
The study will proceed to Phase 2 part only after Phase 1 part demonstrates the tolerability of 
BBI608 combined with Pem plus CDDP based on complete assessment of DLT (with occurrence of 
DLT in no or 1 of 6 patients).  
 
BBI608 will be administered at a dose of 480 mg twice daily (daily dose, 960 mg) in line with the 
overseas RP2D, given that there have been no particular problematic adverse events in overseas 
clinical studies to date and that plasma concentrations showed no profound difference between 
Japanese subjects and non-Japanese subjects.   
 
NSCLC patients are included in the Phase 1 part for preliminary evaluation of the efficacy and 
safety because one of standard therapies is similar between MPM and NSCLC and non-clinical data 
on BBI608 suggest that add-on BBI608 may also be effective in treating NSCLC.   


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5. STUDY OBJECTIVES 
5.1 Phase 1 Part 
 
Primary Objective 
To evaluate the safety, tolerability and pharmacokinetics of BBI608 combined with Pem plus 
CDDP in patients with MPM or NSCLC.  
 
Secondary Objective 
To evaluate the efficacy of BBI608 combined with Pem plus CDDP.  
 
5.2 Phase 2 Part 
 
Primary Objectives 
To evaluate the efficacy and safety of BBI608 combined with Pem plus CDDP in patients with 
MPM.  
 
 
Secondary Objective 
To explore biomarkers related to the efficacy of BBI608.  
 
6. STUDY ENDPOINTS  
6.1 Phase 1 Part 
 
Safety Endpoints  
- Adverse events and adverse drug reactions, DLT 
- Vital signs, body weight  
- Laboratory test values 
- 12-lead ECG  
- Chest X-ray 
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)  
 
 
Efficacy Endpoints  
- Tumor response 
- PFS 
- OS 
- Respiratory function tests (vital capacity [VC], forced vital capacity [FVC], forced 
expiratory volume in the first second [FEV1]) 
 
 
Pharmacokinetic Endpoints  
BBI608 pharmacokinetic parameters of the following:   
- Maximum observed plasma concentration (Cmax)  


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- Minimum observed plasma concentration (Cmin)  
- Area under the plasma concentration-time curve from time zero to 12 hours (AUC0-12)  
- Area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24)  
- Area under the plasma concentration-time curve from time zero to infinity (AUC0-∞)  
- Time to maximum observed plasma concentration (tmax)  
- Terminal elimination rate constant (λz)  
- Terminal elimination half-life (t1/2)  
- Mean residence time (MRT)  
6.2 Phase 2 Part 
 
Efficacy Endpoints  
6.2.1.1 
Primary Endpoint  
- PFS 
 
6.2.1.2 
Secondary Endpoints  
- OS 
- Tumor response (response rate [RR], disease control rate [DCR]) 
RR is defined as the proportion of patients with either Complete Response (CR) or Partial 
Response (PR). DCR is defined as the proportion of patients with CR, PR or Stable Disease 
(SD).  
- Respiratory function tests (VC, FVC, FEV1) 
 
 
Safety Endpoints  
- Adverse events and adverse drug reactions 
- Vital signs, body weight  
- Laboratory test values 
- 12-lead ECG  
- Chest X-ray 
- ECOG PS 
 
 
Other Endpoints  
Biomarkers (β-catenin, phospho-STAT3 [p-STAT3], merlin) 
 
7. INVESTIGATIONAL PLAN  
7.1 Overall Study Design  
This clinical study consists of two parts: Phase 1 and Phase 2. Protocol treatment is defined as 
BBI608 in combination with Pem plus CDDP. Each cycle of protocol treatment consists of 21 days 
(with the exception of Cycle 1 which consists of 23 days). No restriction is set on the number of 


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cycles of protocol treatment. Phase 1 part is conducted in patients with MPM or NSCLC to 
evaluate the safety, tolerability and pharmacokinetics of BBI608 combined with Pem plus CDDP. 
Phase 2 part is conducted in patients with MPM to evaluate the efficacy and safety of BBI608 
combined with Pem plus CDDP. A multicenter, open-label, uncontrolled study design is used for 
both Phase 1 and Phase 2 parts.  
 
 
The study will proceed to Phase 2 part only after Phase 1 part demonstrates the tolerability of 
BBI608 combined with Pem plus CDDP based on complete assessment of DLT (with occurrence of 
DLT in no or 1 of 6 patients). 
 
 
Phase 1 Part 
DLT is first assessed in 3 patients given BBI608 combined with Pem plus CDDP. If DLT occurs in 
0/3 patients, no additional patients are enrolled. If DLT is observed in 1/3 patients, 3 additional 
patients are enrolled and treated. If none of the 3 additional patients experience DLT (i.e., DLT 
occurred in 1/6 patients), no additional patients are enrolled. Figure 1 (page 33) shows the 
flowchart of subject enrollment, and Figure 2 (page 33) shows the flowchart of study procedures in 
individual patients. Patients may be enrolled only after providing consent and being confirmed to 
be eligible. The procedures for enrollment are described in Section 10 (page 42). Administration of 
BBI608 will be started within 14 days after enrollment. If BBI608 therapy is started > 7 days after 
enrollment, repeat baseline examination (ECOG PS, hematology tests, biochemistry tests, and 
urinalysis) is required. In Cycle 1, Day 1 will be the first day of BBI608 administration, and Pem 
and CDDP will be administered on Day 3. DLT will be assessed from Day 1 examination to Day 24 
examination. If treatment is continued to Cycle ≥ 2, re-consent should be obtained between Day 17 
and the start of Cycle 2 therapy. In Cycle 2 and later cycles, Day 1 will be the day of administration 
of Pem and CDDP (or the day of administration of Pem after discontinuation of CDDP in NSCLC 
patients).  
 
The daily dose of BBI608 will be 960 mg which will be orally administered twice daily (morning 
and evening). On Day 1 of Phase 1 part, only the morning dose will be administered. Pem will be 
intravenously administered at 500 mg/m2 by drip infusion over 10 minutes on Day 1 of each 
treatment cycle (except for Cycle 1, in which Pem will be given with an interval of 4 hour after 
BBI608 dosing on Day 3). Premedication with folic acid and vitamin B12 should be given to 
reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. 
Further details are described in Section 10.1 (2) (page 44). CDDP will be intravenously 
administered at 75 mg/m2 by drip infusion over ≥ 2 hours. Each infusion of CDDP will start at 30 
to 50 minutes after a dose of Pem on Day 1 of each treatment cycle (with the exception of Cycle 1 








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7.2 Rationale  
 
Rationale for the Study Design  
The open-label, uncontrolled design was selected because this design will allow for evaluation of 
the safety, tolerability and pharmacokinetics as the objective of Phase 1 part, and also for Phase 2 
part which is exploratory and does not aim to compare the efficacy of this drug and another drug.  
 
 
Rationale for the Dosages  
(1) BBI608 
The dose of BBI608 in this study is set on the basis of the RP2D of BBI608 for monotherapy, 
pharmacokinetics in non-Japanese patients vs. Japanese patients, and metabolism of Pem and 
CDDP.  
 
The RP2D of BBI608 for monotherapy was determined to be 1000 mg/day (500 mg twice daily) 
based on the results of an overseas phase 1 study (Study 101). Subsequently, a new formulation 
containing 80 mg of BBI608 was developed, and thus 960 mg/day (480 mg twice daily) was used 
as the dose nearest to 1000 mg/day in subsequent phase 3 study of BBI608 monotherapy and phase 
3 study of combination therapy with BBI608 and paclitaxel.  
 
Currently in Japan, a phase 1 study of BBI608 monotherapy (D8801001) is ongoing in patients 
with advanced solid cancers. DLT evaluation was completed for all cohorts by 
. 
BBI608 was administered to 3 patients in Cohort 1 (480 mg/day), 4 patients in Cohort 2 (960 
mg/day), and 6 patients in Cohort 3 (1440 mg/day), among whom DLT occurred in no patients 
except 1 patient in Cohort 3 who experienced grade 3 anorexia assessed as DLT. No serious adverse 
events occurred during the DLT evaluation period. Compared with common adverse events in 
overseas clinical studies, i.e., grade 1 or 2 transient diarrhoea, nausea, vomiting or other 
gastrointestinal adverse events, common adverse events in Japanese patients showed no particular 
differences. Comparison of the pharmacokinetics between Japanese patients and non-Japanese 
patients showed that the plasma concentrations in Japanese patients were within the range of 
variation of plasma concentrations in non-Japanese patients. Also, the distribution of Cmax and 
AUC0-24 indicated no substantial difference in the extent of exposure between Japanese patients and 
non-Japanese patients.  
 
Pem and CDDP, which are used in combination with BBI608 in this study, do not inhibit CYP1A2 
as the primary enzyme involved in the metabolism of BBI608.20),21) Although BBI608 inhibits 
CYP1A2, CYP2D6, and other CYP isoforms, CYP enzymes are unlikely involved in the 
metabolism of Pem or CDDP, and thus the use of Pem and CDDP in combination with BBI608 are 
unlikely to cause drug interactions.  


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The recommended dose (RD) of BBI608 for use with Pem plus CDDP was considered to be similar 
to 960 mg/day, i.e., the RD for monotherapy, based on Japanese and overseas clinical studies. Thus, 
the dose of BBI608 in this study is set at the RD of 960 mg/day, for evaluation of the safety, 
tolerability and pharmacokinetics in patients with MPM or NSCLC patients in Phase 1 part, as well 
as the efficacy and safety in patients with MPM in Phase 2 part.  
 
For the method of BBI608 administration, twice daily oral administration at intervals of 
approximately 12 hours was selected with reference to data from ongoing Japanese and overseas 
studies.  
 
For the duration of treatment, daily administration will be continued until discontinuation due to 
adverse events etc., given that BBI608 has little inhibitory effects on normal hematopoietic stem 
cells and nonclinical studies and Japanese and overseas clinical studies have shown favorable 
tolerability of BBI608. Moreover, for patients with MPM, no second-line or subsequent therapies 
with established evidence exist and no standard therapies are available for subsequent treatment. 
For this reason, protocol treatment may be continued until the treatment is no longer clinically 
beneficial to the patient in the opinion of the investigator or subinvestigator.  
The duration of each cycle is set at 21 days (with the exception of Cycle 1 which consists of 23 
days) because this study will use Pem and CDDP that require at least 20 days of dosing intervals 
and are administered on the first day of each 21-day cycle.  
The duration of follow-up observation period is set at 28 days on the basis that the t1/2 of BBI608 
was approximately 8 hours in the phase 1 study of BBI608 monotherapy (Study 101) and 28 days 
would be adequate for safety evaluation after the end of the treatment.  
 
(2) Pem and CDDP 
Pem and CDDP will be administered in accordance with their approved dose and administration 
in Japan. Specifically, Pem will be intravenously administered at 500 mg/m2 by drip infusion over 
10 minutes on Day 1 of each treatment cycle, while CDDP will be intravenously administered at 75 
mg/m2 by drip infusion over ≥2 hours on Day 1 of each treatment cycle, with the exception of 
Cycle 1 in which these drugs will be administered on Day 3 to allow for determination of adverse 
events associated with BBI608.  
  
 
Rationale for the Study Population 
This study will enroll patients with MPM and patients with NSCLC, which are the patient 
populations indicated for the Pem plus CDDP combination chemotherapy.  
 


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Rationale for the Endpoints 
1) Efficacy endpoints  
For MPM, assessment of the treatment efficacy requires measurement of the thickness of 
the tumor lesion in the pleura and thus tumor response will be assessed using the mRECIST 
designed to measure pleura lesion thickness. For NSCLC, tumor response will be assessed 
using the RECIST 1.1 typically used in the assessment of treatment efficacy on solid tumors. 
Tumor response and PFS are used because these are widely used as surrogate endpoints in 
the assessment of efficacy of anticancer drugs. OS is employed for exploratory analysis of 
OS prolongation in this study with a small sample size. FVC and other respiratory function 
tests are used because FVC has been described as an indicator of disease progression or 
improvement in patients with malignant pleural mesothelioma.22) 
2) Safety endpoints  
Commonly used safety endpoints are employed.  
3) Pharmacokinetic endpoints  
Commonly used parameters for pharmacokinetic evaluation are employed.  
4) Other endpoints  
β-catenin, p-STAT3 and merlin are employed for exploratory analysis of the effects of these 
parameters on the efficacy of BBI608.  
 
7.3 Planned Study Period 
February 2015 to May 2018 
 
8. SELECTION OF SUBJECTS 
8.1 Inclusion Criteria  
 
Phase 1 Part 
Patients must fulfil all of the following criteria to be included in this study:  
1) Histologically confirmed diagnosis of MPM or NSCLC 
a) Patients with MPM must meet i) and ii) below:  
i) Treatment naïve and not indicated for surgery  
ii) Evaluable according to the mRECIST  
b) Patients with NSCLC must meet i) and ii) below:  
i) Clinical stage IV [Patients with postoperative recurrence may be included if the interval 
since the end of adjuvant or neoadjuvant chemotherapy (or radiotherapy) is ≥ 180 days 
and if they did not receive Pem or CDDP.]  
ii) Evaluable patients according to the RECIST 1.1 
2) Age ≥ 20 years at the time of consent  
3) Provided written voluntary consent in person to participate in this study after fully receiving 


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and understanding information about the study, including study objectives, contents, 
expected pharmacological effects and foreseeable risks   
4) Agree to use appropriate contraception from the time of consent until 30 days after the last 
dose of the study drug to avoid pregnancy of the female participant or a female partner of 
the male participant   
5) ECOG PS 0 or 1 within 14 days before enrollment  
6) Adequate major organ functions meeting the following criteria based on latest laboratory 
tests within 14 days before enrollment  
- Hemoglobin (Hb) ≥ 9.0 g/dL (without blood transfusion within the preceding 14 days)  
- Neutrophils ≥ 1500/μL 
- Platelets ≥ 100,000/μL 
- AST and ALT ≤ 2.5-fold the upper limit of the normal range of the laboratory (ULN), or 
≤ 5-fold ULN for patients with any liver metastasis  
- Total bilirubin ≤ 1.5-fold ULN 
- Creatinine clearance (estimated value)Note) ≥ 60 mL/min 
Note) Creatinine clearance will be calculated using the Cockcroft-Gault formula shown 
below: Estimated creatinine clearance = (140-age) × body weight / (72 × serum creatinine) 
(× 0.85 for females)  
7) Life expectancy ≥ 3 months 
8) Women of childbearing potential must have a negative pregnancy test (urine) at screening. 
 
 
Phase 2 Part 
1) Histologically confirmed diagnosis of MPM 
2) Treatment naïve and not indicated for surgery  
3) Evaluable according to the mRECIST 
4) Age ≥ 20 years at the time of consent  
5) Provided written voluntary consent in person to participate in this study and tumor tissue 
sampling after fully receiving and understanding information about the study, including 
study objectives, contents, expected pharmacological effects and foreseeable risks  
6) Agree to use appropriate contraception from the time of consent until 30 days after the last 
dose of the study drug to avoid pregnancy of the female participant or a female partner of 
the male participant  
7) ECOG PS 0 or 1 within 14 days before enrollment  
8) Adequate major organ functions meeting the following criteria based on latest laboratory 
tests within 14 days before enrollment  
- Hemoglobin (Hb) ≥ 9.0 g/dL (without blood transfusion within the preceding 14 days)   
- Neutrophils ≥ 1500/μL 
- Platelets ≥ 100,000/μL 


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- AST and ALT ≤ 2.5-fold ULN, or ≤ 5-fold ULN for patients with any liver metastasis  
- Total bilirubin ≤ 1.5-fold ULN  
- Creatinine clearance (estimated value)Note) ≥ 60 mL/min 
Note) Creatinine clearance will be calculated using the Cockcroft-Gault formula shown below:  
Estimated creatinine clearance = (140-age) × body weight / (72 × serum creatinine) (× 
0.85 for females)  
9) Life expectancy ≥ 3 months 
10) Women of childbearing potential must have a negative pregnancy test (urine) at screening 
 
8.2 Exclusion Criteria 
For both Phase 1 and 2 parts, patients meeting any of the following criteria will be excluded from 
this study:  
1) Have received any of the following treatments “a)” to “c)” for the primary disease before 
enrollment in this study 
a) Chemotherapy and surgical therapy (MPM only. excluding surgical biopsy) 
b) Radiotherapy, with the exception of palliative irradiation for pain control or symptomatic 
relief performed within 14 days before enrollment  
c) Hormonal therapy, immunotherapy, thermotherapy, surgical therapy (NSCLC only. 
excluding surgical biopsy), or other antitumor treatments performed within 21 days 
before enrollment 
2) Any brain metastasis requiring treatment or symptomatic  
3) Presence of multiple active cancers at registration  (i.e., synchronous multiple primary 
cancers, or metachronous multiple primary cancers with a disease-free period of ≤5 years, 
with the exception of curatively treated local carcinoma in situ or submucosal carcinoma) 
4) Presence of Crohn’s disease or ulcerative colitis, or have a history of extensive resection of 
the small intestine 
5) Presence of significant 12-lead ECG abnormality within 28 days before enrollment  
6) History of myocardial infarction within 6 months before enrollment   
7) Current use of antiarrhythmic medication, with the exception of anticoagulant therapy for 
atrial fibrillation  
8) Presence of any uncontrolled concurrent disease (e.g., active infection, unstable angina, 
significant respiratory disease) 
9) Known hypersensitivity to Pem, CDDP or other drugs containing platinum  
10) Pregnant or possibly pregnant women, or women planning to breastfeed between the first 
dose of BBI608 to 30 days after the last dose of BBI608  
11) Have received any other investigational drug within 28 days before enrollment in this study   
12) Possible inability to swallow BBI608 for certain reasons such as dysphagia  
13) Previously received BBI608 


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14) Inappropriate for participation in the study for other reasons in the opinion of the 
investigator or subinvestigator  
 
9. STUDY DRUG MATERIALS AND MANAGEMENT 
9.1 Description of Investigational Drug  
The following investigational drug is used in this study:  
Name of investigational drug: BBI608 Capsules 80 mg 
Dosage form and strength: Hard capsules, each containing 80 mg of BBI608 
 
9.2 Investigational Drug Packaging and Labeling
 
Package Description   
Each bottle of the investigational drug contains 84 capsules of BBI608 Capsules 80 mg.  
 
 
Labeling Description  
Each bottle of the investigational drug is labeled with the following information: statement of “For 
use in a clinical trial”, investigational substance code (BBI608), lot number, expiration date, storage 
condition, sponsor’s name and address.  
 
9.3 Investigational Drug Storage  
Store in a tight, light-resistant container at 2 to 25°C. 
 
9.4 Dispensing of Investigational Drug  
The investigator or subinvestigator will dispense the investigational drug to each subject in light of 
the inpatient/outpatient status of the subject so that the subject can take the protocol-specified 
amount of the investigational drug. Subjects treated as outpatients should be given adequate 
explanation about the handling of the investigational drug as well as instructions on how to store 
and take the drug appropriately.  
 
9.5 Investigational Drug Accountability  
After the study contract is signed between the sponsor and the medical institution, the sponsor will 
deliver the investigational drug to the investigational drug manager. The investigational drug 
manager of the medical institution will store and manage the investigational drug according to the 
written procedures for management of the investigational drug, and prepare the investigational drug 
accountability log to keep track of the use of the investigational drug. The investigational drug must 
not be used for other purposes than this study.  
 


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9.6 Investigational Drug Handling and Disposal  
The investigational drug manager of the medical institution will handle the investigational drug 
according to the written procedures for handling of the investigational drug. Any investigational 
drug unused or returned from the subjects must be returned to the sponsor from the investigational 
drug manager according to the written procedures for management of the investigational drug. If 
the investigational drug is inadvertently discarded or lost at the medical institution, the 
investigational drug manager will document it in the investigational drug accountability log and 
report it to the sponsor.  
 
The investigational drug manager will submit a copy of the investigational drug accountability log 
to the sponsor after the end of treatment with the investigational drug. The sponsor will check the 
consistency between the investigational drug accountability log and the number of the 
investigational drug unused or returned from the subjects and the entries in the eCRF. Any 
inconsistency should be immediately investigated and addressed as necessary by the investigator or 
subinvestigator.  
 
The sponsor will retrieve any unused investigational drug in principle before the expiration date as 
a measure to ensure that no subjects receive the investigational drug after the expiration date. If the 
retrieval is after the expiration date, the investigational drug manager of the medical institution will 
separately store the expired investigational drug from the non-expired investigational drug.  
 
10. TREATMENT OF SUBJECTS 
1) The investigator or subinvestigator will assign a Subject Identification Code to each of the 
individuals who have provided the informed consent.  
2) The investigator or subinvestigator will assess the eligibility of subjects against the 
inclusion and exclusion criteria before enrollment.  
3) Individual subjects are enrolled according to the procedures in Figure 5 (page 44). For 
enrollment of subjects meeting the eligibility, the investigator, subinvestigator or clinical 
research coordinator will facsimile the “Subject Enrollment Form” to the sponsor. The 
sponsor will confirm the eligibility of each subject based on the “Subject Enrollment Form” 
and facsimile the “Enrollment Confirmation Form” to the investigator or subinvestigator to 
notify the result of enrollment assessment and Subject Number for the subject.  
4) Hospitalization (Phase 1 part only)  
The investigator or subinvestigator will admit the subject to the study site for 
pharmacokinetic sampling (i.e., Days 1 to 4, 23 and 24 of Cycle 1), if necessary from the 
day before pharmacokinetic sampling.  
5) Confirmation of eligibility just before BBI608 administration 


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Just before the start of BBI608 administration, the investigator and subinvestigator will 
confirm the following:  
- Completion of baseline examination specified in the study schedule (Table 2 on page 10 
orTable 5 on page 16)  
- No presence of any new test findings obtained after the last eligibility assessment that 
would require exclusion of the subject according to the inclusion or exclusion criteria.   
6) Any discontinuation before the start of BBI608 administration 
If the subject is discontinued from the study between enrollment and the start of BBI608 
administration, the investigator, subinvestigator or clinical research coordinator will 
facsimile the “Pre-treatment Withdrawal Report Form” to the sponsor to notify the 
withdrawal. The sponsor will take the withdrawal procedure.  
 
Where to contact for Subject Enrollment:  
Group 2, Oncology Clinical Development Office  
Sumitomo Dainippon Pharma Co., Ltd. 
Address: 1-17-10 Kyobashi, Chuo-ku, Tokyo 104-0031 
Office hours: 9:00–18:00, Monday through Friday (Closed on Saturdays, Sundays, national 
holidays, and from December 29 to January 4)  
Fax: 03-5159-2946 
Tel: 03-5159-2518 


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Figure 5  Subject Enrollment Procedures 
Study site 
Sponsor  
Determination of potential subjects 
Informed consent 
Screening (Inclusion/Exclusion Criteria) 
 
 
Fax Subject Enrollment Form 
 
 
 
 
 
 
 
 
 
Receive Enrollment Confirmation Form 
 
 
 After confirmation of eligibility, start 
BBI608 administration 
 
 
<If BBI608 therapy is not started> 
Fax Pre-treatment Withdrawal Report 
Form 
 
 
 
 
 
Receive Subject Enrollment Form 
 
 
Eligibility check 
 
Eligible              Not eligible  
 
 
 Enrollment           No enrollment 
 
Fax Enrollment Confirmation Form 
 
 
 
 
 
 
 
Receive Pre-treatment Withdrawal Report 
Form 
 
10.1 Study Medication  
(1) BBI608 
BBI608 will be orally administered at a dose of 480 mg twice daily (morning and evening) (daily 
dose, 960 mg). Each dose will be taken at either 1 hour before or 2 hours after a meal, with dosing 
intervals of approximately 12 hours. On Day 1 of Phase 1 part, however, only the morning dose 
will be administered. Subjects should be advised to drink an adequate amount of fluid when taking 
BBI608.  
 
(2) Pemetrexed (Pem)  
Pem, as a marketed product, will be intravenously administered at 500 mg/m2 by drip infusion over 
10 minutes on Day 1 of each treatment cycle (except for Cycle 1, in which Pem will be given on 
Day 3). Meanwhile, Pem will be administered with an interval of at least 4 hours after BBI608 
dosing in Cycle 1 of phase 1 part only. Premeditation with folic acid and vitamin B12 should be 
given as described below to reduce occurrence of serious adverse drug reactions, with reference to 
the package insert for Pem.  
1) Folic acid 


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Folic acid (as a marketed product) will be orally administered at 0.5 mg once daily, starting 
≥ 7 days before the initial dose of Pem. When Pem therapy is discontinued or completed, 
folic acid administration will be continued until 22 days after the last dose of Pem as far as 
possible.  
2) Vitamin B12 
A dose of vitamin B12 (as a marketed product) 1 mg will be intramuscularly administered 
≥ 7 days before the initial dose of Pem. Vitamin B12 dosing will then be repeated every 9 
weeks during Pem therapy and until 22 days after the last dose of Pem.  
 
(3) Cisplatin (CDDP)  
CDDP, as a marketed product, will be intravenously administered at 75 mg/m2 by drip infusion 
over ≥2 hours. Each infusion of CDDP will start at 30 to 50 minutes after a dose of Pem. To reduce 
nephrotoxicity of CDDP, fluid infusion, diuretic therapy, and other treatments should be given, with 
reference to the package insert for CDDP.  
 
10.2 Criteria for Protocol Treatment Modification  
When discontinuation of Pem or CDDP is required by an adverse event etc. in the opinion of the 
investigator or subinvestigator, both Pem and CDDP should be discontinued, while only BBI608 
will be continued. When discontinuation of BBI608 is required, the subject will be withdrawn from 
the study. For NSCLC patients in Phase 1 part, however, only CDDP may be discontinued at the 
discretion of the investigator or subinvestigator.23) 
 
(1) BBI608 
Possible adverse events associated with BBI608 include gastrointestinal disorders (nausea, 
diarrhoea, abdominal colic) and fatigue on the basis of previous clinical studies. If any adverse 
event occur and treatment suspension or dose reduction is judged required, the following <Method 
of treatment suspension and dose reduction (Recommendations)> shall be referred. 
 
<Method of treatment suspension and dose reduction (Recommendations)> 
Table 7 (page 46) shows BBI608 dosage modifications, and Table 8 (page 47) summarizes 
recommended interventions for management of adverse events.  
 
Adverse events will be graded according to the National Cancer Institute - Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0, Japanese translation by Japanese Clinical 
Oncology Group (NCI CTCAE v4.0-JCOG). For a subject experiencing multiple adverse events for 
which recommended measures differ, the lowest recommended dose should be selected.  
 










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No restriction is set on the number of cycles. Administration of BBI608 will be started 
within 14 days after enrollment. DLT will be assessed following the start of BBI608 
administration on Day 1 of Cycle 1 and until Day 24 pre-dose examination in Phase 1 part.  
 
Protocol treatment will be continued in the following manner:  
- Only in Phase 1 part, voluntary written re-consent to continue treatment should be obtained 
from the subject between Day 17 of Cycle 1 and the start of Cycle 2.  
- Protocol treatment with the three drugs should be repeated as long as possible; no restriction 
is set on the number of cycles. 
- If an adverse event associated with either Pem or CDDP is judged to require treatment 
discontinuation, both Pem and CDDP should be discontinued, while BBI608 will be 
continued as long as possible. For NSCLC patients, however, only CDDP may be 
discontinued at the discretion of the investigator or subinvestigator.23)  
- Even after assessment of PD according to the RECIST 1.1 or mRECIST, administration of 
BBI608 may be continued until the treatment is no longer clinically beneficial to the 
patient in the opinion of the investigator or subinvestigator for certain reasons such as 
intolerable adverse events or further progression of the primary disease. 
2) Follow-up observation period 
The follow-up observation period is defined as the period from the day of the last dose of 
BBI608 
until 
the 
examination/observation 
28 
days 
later, 
or 
until 
the 
examination/observation before subsequent treatment if subsequent treatment is given 
within 28 days after the last dose of BBI608.  
3) Patient outcome investigation  
Patient outcome investigation will be continued until 6 months and 1 year after last 
subject’s treatment start date. 
4) Subsequent treatment  
No restriction is set on subsequent treatment.  
 
10.5 Definition of DLT and Enrollment of Additional Subjects (Phase 1 Part)  
DLT will be assessed in Phase 1 part and not in Phase 2 part.  
 
 Definition of DLT 
DLT is defined as an adverse event meeting any of the following that occurred during the DLT 
evaluation period in any subjects given BBI608 with the causal relationship to BBI608 assessed as 
“Definite,” “Probable,” or “Possible.” The severity of adverse events will be graded according to 
the CTCAE v4.0-JCOG. The investigator and the sponsor will discuss to determine any DLT in 
individual subjects. As necessary, the sponsor will seek opinion of the Data and Safety Monitoring 


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Board to determine DLT.  
- Grade 4 neutropenia persisting for ≥ 7 days 
- Grade ≥ 3 febrile neutropenia persisting for ≥ 5 days  
- Grade 3 thrombocytopenia requiring platelet transfusions, grade 4 thrombocytopenia  
- Grade ≥ 3 non-hematotoxicity except the following:  
a) Inappetence, nausea, vomiting and electrolyte abnormality which, within 3 days of onset, 
improved to grade ≤ 2 or resolved after appropriate treatment  
b) Diarrhoea and fatigue which, within 5 days of onset, improved to grade ≤ 2 or resolved 
after appropriate treatment  
- Other clinically significant signs in the opinion of the investigator 
 
 DLT Evaluation Period and Subjects Evaluated for DLT  
The DLT evaluation period is defined as the period following administration of BBI608 on Day 1 
of Cycle 1 until Day 24 pre-dose examination. DLT evaluation will be performed in subjects given 
BBI608 who meet either of the following:  
- Subjects with a ≥ 80% BBI608 treatment compliance rate during the DLT evaluation period, 
as calculated by the following formula:  
[Amount of BBI608 actually taken/(Protocol-specified dose* × 45)] × 100 (%) 
*Protocol-specified dose = 480 mg 
- Subjects with onset of DLT irrespective of the BBI608 treatment compliance rate  
 
 Enrollment of Additional Subjects  
Criteria for enrollment of additional subjects are as follows (see Figure 1, page 33).  
- If any of the first 3 patients started on study treatment are not assessable for DLT, the 
patient(s) will be replaced by new patient(s). 
- If DLT occurs in 0/3 patients, no additional patients are enrolled.  
- If DLT occurs in 1/3 patients, 3 additional patients are enrolled.  
- If DLT occurs in ≥ 2/3 patients, the enrollment is stopped.  
- If DLT occurs in ≥ 2/3 or ≥ 2/6 patients, the sponsor will discuss with the investigator to 
decide whether or not to continue already ongoing treatment in subjects currently in the 
study. As necessary, the sponsor will seek opinion of the Data and Safety Monitoring Board.   
- If the sponsor judges that more than 3 patients are required for assessment of the 
pharmacokinetics or safety, additional patients may be enrolled up to a total of 6, as 
necessary based on discussion with a coordinating investigator etc.   
 
10.6 Concomitant Medications and Therapies  
For the period from the start of study treatment to final evaluation in the follow-up observation 


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period, details of any concomitant medications (i.e., name of drug, route of administration, therapy 
dates, reason for use) and concomitant therapies (i.e., name of therapy, therapy dates, reason for 
use) will be recorded in the eCRF. For the following drugs, however, no recording in the eCRF is 
required (unless they caused adverse events).  
- Drugs used for examinations (e.g., contrast agents, premedication, post-examination 
medication)  
- Local anaesthesia (e.g., for tooth extraction)  
- Preparations used for dilution (e.g., physiological saline)  
- Fluid preparations used for other purposes than treating adverse events (e.g., heparin lock to 
prevent blood coagulation)  
 
 Prohibited Concomitant Medications and Prohibited Concomitant Therapies  
From the date of enrollment until the date of last dosing, the following treatments will be 
prohibited.  
1) Anticancer chemotherapy (other than Pem and CDDP as the components of protocol 
treatment), radiotherapy, hormonal therapy, immunotherapy, thermotherapy, surgical therapy, 
or other therapies for cancer 
2) Other investigational drugs, post-marketing clinical study drugs, or drugs unapproved in 
Japan  
3) Therapies with immunosuppressive effects (e.g., systemic steroids), with the exception of 
the following:  
- Intermittent use for antiemesis 
- Use at a less-than-immunosuppressive dose for malaise or appetite loss 
- Prophylactic use after onset of rash 
4) Until the end of the DLT evaluation period in Phase 1 part, prophylactic use of granulocyte 
colony stimulating factor (G-CSF) products    
 
 Restricted Concomitant Medications 
Drugs listed in “1)” to “3)” below should be in principle avoided from the date of initial dosing of 
BBI608 until the date of last dosing of BBI608, unless clinically required in the opinion of the 
investigator or subinvestigator. Drugs listed in “4)” below should be avoided from 2 or 5 days 
before Pem administration until 2 days after Pem administration. The investigator or 
subinvestigator will also instruct subjects to avoid consumption of products containing the 
following that could affect the metabolism of BBI608 by inhibiting or inducing CYP1A2: tobacco, 
herbs (e.g., St. John’s wort, Ginkgo), caffeine-rich beverages and food, burnt meat, Brussels 
sprouts.  
 


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1) Substrates of CYP1A2, 2D6, 2C19, 3A4, or 2C9, including but not limited to the following:  
- Non-steroidal anti-inflammatory drugs: ibuprofen, diclofenac, celecoxib, etc.  
- Proton-pump inhibitors: lansoprazole, omeprazole, etc. 
- Oral hypoglycemic agents: sulfonylureas, etc.  
- β-blockers: propranolol, metoprolol, etc.  
- Calcium antagonists: amlodipine, diltiazem, nifedipine, verapamil, felodipine, nisoldipine, 
etc.  
- Antidepressants: paroxetine, imipramine, amitriptyline, duloxetine, etc.  
- Antiepileptics: phenytoin, etc.  
- Antipsychotics: haloperidol, risperidone, quetiapine, perphenazine, pimozide, etc.  
- Antibiotics: clarithromycin, erythromycin, etc.  
- HMG CoA reductase inhibitors: atorvastatin, simvastatin, etc.  
- Anesthetics: fentanyl etc.  
- Anti-HIV drugs: saquinavir, indinavir, ritonavir, darunavir, etc.  
- Steroids: hydrocortisone, estradiol, budesonide, fluticasone, etc.  
- Antiemetics and antidiarrheals: aprepitant, etc.  
2) CYP1A2 inhibitors, including but not limited to the following:  
Ciprofloxacin and other fluoroquinolone antimicrobials, fluvoxamine, verapamil, 
amiodarone, mexiletine, interferon, methoxsalen, ticlopidine, progestogen and estrogen 
drugs (oral contraceptives), acyclovir, allopurinol, cimetidine, disulfiram, famotidine, 
norfloxacin, propafenone, propranolol, terbinafine, etc.  
3) CYP1A2 inducers, including but not limited to the following 
Montelukast, phenytoin, omeprazole, phenobarbital, etc.  
4) Non-steroidal anti-inflammatory drugs (NSAIDs)  
In patients with mild to moderate renal impairment (defined as creatinine clearance 45–89 
mL/min), NSAIDs with short half-life should be avoided for 5 days from 2 days before Pem 
administration until 2 days after Pem administration.  
In all subjects irrespective of renal impairment, NSAIDs with long half-life should be 
avoided for 8 days from 5 days before Pem administration until 2 days after Pem 
administration.  
- 
NSAIDs with short half-life include, but not limited to, ibuprofen and aspirin.  
- 
NSAIDs with long half-life include, but not limited to, nabumetone, naproxen, and 
piroxicam.  
 
 Permitted Concomitant Medications 
Drugs and therapies not listed in Section 10.6.1 (page 52) or Section 10.6.2 (page 52) are permitted 
for concomitant use.  


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<Examples of permitted concomitant drugs and therapies> 
- Symptomatic therapy and supportive therapy to relieve a symptom of the primary disease   
- Treatment of a concurrent disease  
- Treatment of an adverse event  
- Premedication before administration of Pem and CDDP to reduce occurrence of serious 
adverse drug reactions 
- G-CSF to treat neutropenia (in patients with febrile neutropenia or grade 4 neutropenia, or 
in patients with grade 3 neutropenia who had febrile neutropenia or grade 4 neutropenia 
in the previous cycle)  
  
10.7 Restrictions  
Subjects will be hospitalized to undergo pharmacokinetic sampling (i.e., Days 1 to 4, 23 and 24 of 
Cycle 1 of Phase 1), if necessary from the day before pharmacokinetic sampling. All other study 
procedures may be performed on an outpatient basis.  
 
10.8 Contraception Requirements 
Female subjects of childbearing potential and male subjects with female partners must avoid 
pregnancy by sexual abstinence or use of appropriate contraception from the time of consent until 
30 days after the last dose of the study drug. Appropriate contraceptive measures available in Japan 
include condoms, oral contraceptive pills, pessaries, intrauterine devices and systems, vasectomy, 
and tubal ligation.  
 
10.9 Treatment Assignment and Blinding 
No randomization will occur in this open-label study. Both Phase 1 and Phase 2 parts will use the 
same starting doses.  
 
11. STUDY ASSESSMENTS 
The flowchart of study procedures in individual subjects in Phase 1 and Phase 2 parts is shown in 
Figure 2 (page 33) and Figure 4 (page 35), respectively. The schedule of investigations, 
observations and examinations in Phase 1 and Phase 2 parts is shown in Table 2 (page 10) and 
Table 5 (page 16), respectively. Investigations, observations and examinations and assessments will 
be performed at the scheduled time points, which are based on Day 1 of treatment in the subject as 
defined below.  
 
In Cycle 1, Day 1 will be the first day of BBI608 administration. In Cycle 2 and later cycles, Day 1 
will be the day of administration of Pem and CDDP (or the day of administration of Pem after 
discontinuation of CDDP in NSCLC patients in Phase 1 part).  


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Obtained clinical findings and results of observations and examinations and assessments will be 
recorded in source documents. For the items specified below, the dates of measurements and results 
after baseline examination will be recorded in the eCRF.  
 
11.1 Demographic and Baseline Characteristics  
Before the start of study treatment, the following data will be collected and recorded in the eCRF.  
 
 Phase 1 Part 
1) Demographic data 
- Sex, date of birth, race, ethnicity 
- Height, body weight  
2) Disease data  
- ECOG PS 
- Clinical Stage (Stage I, II, IIIA, IIIB, IV)  
- Diagnosis (MPM, NSCLC)  
- Histological type 
MPM: Epithelioid, sarcomatoid, biphasic, other (specify)  
NSCLC: Adenocarcinoma, squamous cell carcinoma, large cell carcinoma, other 
(specify)  
- Sites of metastases 
- Concurrent disease, symptoms associated with the primary disease 
- Date of diagnosis of the primary disease  
3) Other  
- Subject Identification Code, Subject Number 
 
For female subjects, the investigator or subinvestigator should confirm the status of menopauseNote) 
and pregnancy before enrollment. Women before menopause will undergo pregnancy testing (urine) 
within 3 days before the start of study treatment.  
Note) Menopause is defined as no occurrence of menstruation for 12 months or more without any medical reason 
(e.g., chemical menopause).  
 
 
 Phase 2 Part 
1) Demographic data 
- Sex, date of birth, race, ethnicity 
- Height, body weight  
2) Disease data  


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- ECOG PS 
- Clinical stage (Stage I, II, IIIA, IIIB, IV)  
- Histological type (epithelioid, sarcomatoid, biphasic, other [specify]) 
- Sites of metastases 
- Concurrent diseases, symptoms associated with the primary disease 
- Date of diagnosis of the primary disease 
3) Other  
- Subject Identification Code , Subject Number 
 
For female subjects, the investigator or subinvestigator should confirm the status of 
menopauseNote) and pregnancy before enrollment. Women before menopause will undergo 
pregnancy testing (urine) within 3 days before the start of study treatment.  
Note) Menopause is defined as no occurrence of menstruation for 12 months or more without 
any medical reason (e.g., chemical menopause). 
 
11.2 Efficacy Assessments 
 Tumor Response 
11.2.1.1 Imaging Data Items  
For imaging, the investigator or subinvestigator will collect the following data and record them 
in the eCRF. If tumor enlargement is clinically suspected, radiological examination such as CT or 
MRI should be performed for confirmation.  
- Presence or absence of target lesions, organs of all selected target lesions, specific sites of 
lesions, size of lesions, imaging modality (CT, MRI, other), date of imaging  
- Presence or absence of non-target lesions, organs of all non-target lesions, imaging modality 
(CT, MRI, other), date of imaging 
- Presence or absence of new lesions, organ  
- Assessment of overall response, date of imaging used for the assessment  
- Best overall response 
 
11.2.1.2 Imaging Assessments  
11.2.1.2.1 Tumor Lesion Measurements  
Imaging (CT, MRI or other) of tumor lesions will be obtained before the first dose of BBI608 
(within 14 days before enrollment), every 6 weeks (±1 week) from the first dose of BBI608 (Day 1 
of Cycle 1) until Week 30, and every 9 weeks (±1 week) from Week 31 on. The schedule of 
imaging is based only on Day 1 of Cycle 1, irrespective of Day 1 of Cycle 2 or any later cycle. The 
imaging modality used at baseline should be used throughout the study. For CT, the slice thickness 
must be ≤ 5 mm. Tumor measurements and evaluations will be performed according to the RECIST 


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1.1 for NSCLC or other carcinomas than MPM, and mRECIST for MPM.  
 
11.2.1.2.2 Tumor Response and Overall Response  
The study site and the imaging assessment committee (only the study site in Phase 1 part) will 
evaluate the tumor response and overall response based on imaging. In Phase 2 part, the results by 
the imaging assessment committee will be used as the results of final imaging assessment.  
 
(1) RECIST1.1 
The RECIST 1.1 will be used for the evaluation of tumor response and overall response in patients 
with NSCLC, and also the evaluation of any non-pleural lesions in patients with MPM. Baseline 
imaging will be obtained before the first dose of BBI608 (within 14 days before enrollment).  
 
1) Selection and evaluation of target lesions 
For target lesions, all lesions up to a maximum of five lesions total (and a maximum of two 
lesions per organ) representative of all involved organs should be identified. Target lesions 
should be selected on the basis of their size at baseline, and lend themselves to reproducible 
repeated measurements.  
2) Evaluation of non-target lesions 
All other lesions than those selected as target lesions are non-target lesions, whether or not 
measurable.  
3) Determination and recording of response  
For each imaging, the results of evaluation of target lesions (CR, PR, SD, PD, NE), 
evaluation of non-target lesions (CR, Non-CR/Non-PD, PD, NE), presence or absence of 
new lesions (if yes, specific site of the lesion), and overall response are recorded along with 
the date of imaging in the eCRF. At final assessment, best overall response (CR, PR, SD, 
PD, NE) will also be recorded in the eCRF. For a subject with no measurable lesions at 
baseline and with an overall response of “Non-CR/Non-PD,” the overall response should be 
converted to “SD” in the assessment of best overall response. For determination of SD in 
terms of best overall response, the subject must fulfil the criteria for SD at least once based 
on Week 6 imaging or later imaging.  
 
(2) mRECIST for MPM 
The mRECIST will be used for the evaluation of tumor response and overall response in patients 
with MPM.24) Baseline imaging will be obtained before the first dose of BBI608 (within 14 days 
before enrollment).  
 
1) Selection and evaluation of target lesions 


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For target lesions, all lesions up to a maximum of 10 lesions total representative of all 
involved organs should be identified. Target lesions should be selected on the basis of their 
size, and lend themselves to reproducible repeated measurements. Of these, up to 6 lesions 
will be selected based on baseline evaluation as far as possible. For pleura lesions, the 
cross-sectional longest tumor thickness perpendicular to the chest wall or mediastinum will 
be measured.  
2) Evaluation of non-target lesions 
All other lesions than those selected as target lesions are non-target lesions, whether or not 
measurable.  
3) Determination and recording of response  
For each imaging, the results of evaluation of target lesions (CR, PR, SD, PD, NE), 
evaluation of non-target lesions (CR, Non-CR/Non-PD, PD, NE), presence or absence of 
new lesions (if yes, specific site of the lesion), and overall response are recorded along with 
the date of examination in the eCRF. At final assessment, best overall response (CR, PR, SD, 
PD, NE) will also be recorded in the eCRF. For a subject with no measurable lesions at 
baseline and with an overall response of “Non-CR/Non-PD,” the overall response should be 
converted to “SD” in the assessment of best overall response. For determination of SD in 
terms of best overall response, the subject must fulfil the criteria for SD at least once based 
on Week 6 imaging or later imaging.  
 
11.2.1.2.3 Submission of Imaging Data 
Only in Phase 2 part, the investigator or subinvestigator will submit a copy of the imaging data 
used for evaluations in Section 11.2.1.2 (page 56). The study site shall put masking on information 
which may identify subjects, such as allocating subject ID codes, when providing the copies of 
imaging data. 
 
11.2.1.2.4 Imaging Assessment Committee  
In Phase 2 part, the imaging assessment committee will evaluate the tumor response and overall 
response in accordance with separately prepared written procedures, on the basis of the submitted 
imaging data.  
 
 Patient Outcome  
Patient outcome (alive, dead, unknown), cause of death if dead (progression of the primary disease, 
other) and date of death, date of confirmation of patient outcome, any subsequent treatment and its 
details (chemotherapy [drug names], surgical therapy, radiotherapy, other) and therapy start date 
and end date will be investigated until 6 months and 1 year after last subject’s treatment start date, 
and recorded in the eCRF. However, the patient outcome investigation may be continued beyond 1 


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year if judged necessary by the sponsor.  
 
 Respiratory Function Tests  
VC, FVC, FEV1, and dates of testing  
 
11.3 Safety Assessments  
 Adverse Events 
Adverse events will be collected for each subject. Subjects should be queried in a non-leading 
manner, without specific prompting (e.g., “Has there been any change in your health status since 
your last visit?”) (See Section 12, page 62). 
 
Adverse events and serious adverse events will be monitored throughout the study at all visits 
(including telephone interviews).  
 
 DLT (Phase 1 Part)  
DLT will be assessed as described in Section 10.5 (page 50).  
 
 Clinical Laboratory Tests 
Clinical laboratory tests listed below will be performed in this study. Blood and urine specimens for 
laboratory tests will be collected and the dates will be recorded. All laboratory tests will be 
performed locally by the laboratory of the study site. For specific procedures for laboratory tests 
and sampling and shipping, written instructions by the laboratory of the study site should be 
observed.  
- Hematology: white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet 
count, white blood cell differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes)  
- Biochemistry: total protein, albumin, total bilirubin, AST, ALT, ALP, LDH, BUN, creatinine, 
Na, K, Cl, Ca, Mg 
- Urinalysis (qualitative): glucose, protein, occult blood  
 
 Vital Signs and Body Weight  
Blood pressure, pulse rate, body temperature (axillary), and body weight will be recorded with the 
dates of measurements.  
 
 Chest X-ray 
X-ray results (assessmentNote) and abnormal findings if any) will be recorded with the dates of 
X-rays.  


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Note) Assessment: Normal, Abnormal (not clinically significant), Abnormal (clinically significant)  
 
 12-lead ECG  
ECG results (assessmentNote) and abnormal findings if any) will be recorded with the dates of 
ECG. 
Note) Assessment: Normal, Abnormal (not clinically significant), Abnormal (clinically significant)  
 
 ECOG PS 
The ECOG PS score will be recorded.   
 
11.4 Pharmacokinetic Assessments (Phase 1 Part)  
  Plasma Drug Concentrations  
1) Analytes  
- Plasma BBI608 concentration  
- Plasma Pem concentration  
- Plasma CDDP concentration  
2) Time points of the measurement of plasma BBI608 concentration 
- Days 1 and 2 of Cycle 1 (8 time points)  
Before the morning dose of BBI608, and at 2, 4, 6, 8, 10, 12, and 24 hours (i.e., 
pre-morning dose on Day 2)  
- Day 3 of Cycle 1 (3 time points)  
Before the morning dose of BBI608, immediately before Pem administration, before the 
evening dose of BBI608 
- Days 23 and 24 of Cycle 1 (8 time points)  
Before the morning dose of BBI608, and at 2, 4, 6, 8, 10, and 12 (i.e., pre-BBI608 
evening dose), and 24 (pre-BBI608 morning dose on Day 24) hours 
3) Time points of the measurement of plasma Pem concentration 
- Day 3 of Cycle 1 (3 time points)  
Immediately before Pem administration, immediately after Pem administration, before 
the evening dose of BBI608 on Day 3 
4) Time points of the measurement of plasma CDDP concentration 
- Days 3 and 4 of Cycle 1 (3 time points)  
Immediately before or immediately after Pem administration or immediately before 
CDDP administration, immediately after CDDP administration, and before the morning 
dose of BBI608 on Day 4  
5) Blood sampling volume and method  
A total of 75 mL of blood will be collected from each subject (using an anticoagulant 
EDTA-2K). Specifically, plasma BBI608 concentration measurements will require 3 mL 


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each of blood at 19 time points. Plasma Pem concentration measurements will require 3 mL 
each of blood at 3 time points. Plasma CDDP concentration measurements will require 3 
mL each of blood at 3 time points.   
6) Blood specimen processing  
The collected blood specimens will be processed according to the written procedures 
prepared separately.  
7) Documentation of blood sampling, meals, BBI608/Pem/CDDP administration, and 
anti-nephrotoxic fluid infusion, and results of drug concentration measurements 
The investigator or subinvestigator will record the following information in the eCRF 
according to Table 4 (page 14).  
- Date and time of blood sampling  
- Date and time of meals  
- Date and time of BBI608 administration, number of capsules taken  
- Date and the start time and end time of each dosing of Pem and CDDP 
- Date and the start time and end time of each fluid infusion for Pem/CDDP nephrotoxicity 
prophylaxis 
 
The laboratory responsible for pharmacokinetic measurements will retrieve the specimens 
for drug concentration measurements, measure the plasma drug concentrations, and prepare 
the measurement result reports.  
 
 Exploratory Analysis of Metabolites in Plasma  
When necessary, the sponsor may analyze metabolites in plasma in an exploratory manner using 
residual specimens. If any exploratory plasma metabolite analysis is performed, the results will not 
be contained in the clinical study report but a separate report will be prepared.  
 
11.5 Biomarkers  
1) Target patient population  
Patients with a histological diagnosis of MPM (in Phase 2 part only)  
2) Biomarkers to be measured  
- β-catenin 
- Phospho-STAT3 (p-STAT3)  
- Merlin 
3) Methods of specimen collection and measurements  
From the available tumor tissue collected for the diagnostic purpose, 6 or more histology 
slides will be prepared and sent to the sponsor. The retrieval and staining of tumor tissue 
specimens will be performed according to the written procedures prepared separately by the 


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laboratory responsible for biomarker measurements.  
4) Timing and method of specimen submission  
The samples and copies of pathology reports will be sent to the sponsor on or after the date 
of enrollment of the patient as appropriate, after patient-identifiable information is removed 
and replaced by the Subject Identification Code etc. at the study site. 
5) De-identification of patients  
A unique Subject Identification Code will be assigned to each subject at the study site, 
which meets the standards for secure privacy protection in this clinical study. No further 
de-identification measures are taken.  
6) Histopathological assessment  
A pathological assessment committee will be formed to perform the histopathological 
assessment. The histopathological assessment will be performed in accordance with 
separately prepared written procedures.  
7) Reporting of the histopathological assessment results  
The sponsor will notify the investigator or subinvestigator of the histopathological 
assessment results by the pathological assessment committee.  
8) Documentation in the eCRF 
The investigator or subinvestigator will record the date of tumor tissue collection in the 
eCRF.  
9) Specimen disposal  
The sponsor will be responsible for destroying the submitted de-identified histology slides 
within 10 years after the end of this clinical study, while the slides remaining de-identified. 
For subjects who have withdrawn their consent to slide provision, the slides will be 
immediately destroyed.  
 
12. SAFETY REPORTING 
12.1 Definitions  
 Adverse Events 
An adverse event is any untoward medical occurrence in a study subject administered an 
investigational drug and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease occurring after the administration of an investigational 
drug, whether or not considered related to the investigational drug. Adverse events may include the 
onset of new illness and the exacerbation of pre-existing conditions.  
 
In this study, adverse events refer to those occurring between initial dosing of the investigational 
drug and final evaluation in the follow-up observation period, as well as other unfavorable events 


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during the study period (e.g., events outside the treatment period [during the follow-up observation 
period etc.], events related to a study procedure or assessment).  
 
Lack of efficacy may be an expected potential outcome and should not be reported as an adverse 
event unless the event is unusual in some way. Worsening of the primary disease or a metastasis of 
the primary disease should not be reported as an adverse event. 
 
The investigator or subinvestigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the adverse event, and not the individual signs/symptoms. 
 
 Serious Adverse Events 
A serious adverse event (SAE) is an AE that meets one or more of the following criteria:  
• 
Results in death.  
• 
Is life-threatening (i.e., a patient is at immediate risk of death at the time of the event, not 
an event where occurrence in a more severe form might have caused death).  
• 
Requires hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event that may jeopardize the subject or may require a medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization. 
 
The term “serious” is used for events that pose a threat to a subject’s life or functioning as defined 
by the criteria above.  
 
During the study, if a subject has a hospitalization or procedure that was scheduled before the 
informed consent to this study because of a pre-existing condition since before participation in the 
study, the hospitalization is considered a therapeutic intervention and not the result of a serious 
adverse event. However, if the pre-existing condition worsens during the study, it should be 
reported as an adverse event (or serious adverse event if the condition results in a serious outcome 
such as prolongation of hospitalization). 
 
Life-threatening means that the subject was, in the view of the investigator or subinvestigator, at 
immediate risk of death from the event as it occurred. This definition does not include an event that 


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had it occurred in a more severe form might have caused death. 
 Adverse Drug Reactions 
Adverse drug reactions are defined as adverse events assessed to be related to the investigational 
drug.  
 
12.2 Abnormal Findings  
Clinically significant abnormal findings (e.g., results of laboratory tests, ECG, chest X-ray and 
physical examination) will also be recorded as adverse events.  
 
When a clear diagnosis is available that explains the findings, the diagnosis will be recorded as the 
adverse event, and not the abnormal findings (e.g., viral hepatitis will be recorded as the adverse 
event, not transaminase elevation). If a definite diagnosis is not available, then record the sign (e.g., 
clinically significant transaminase elevation) or symptom (e.g., abdominal pain).  
 
The investigator or subinvestigator will review laboratory test results, and determine the clinical 
significance of all out-of-range values. Clinical laboratory tests with possibly drug-related or 
clinically relevant abnormal values of uncertain causality may be repeated. Any abnormal values 
that persist should be followed at the discretion of the investigator or subinvestigator. Laboratory 
reports will be signed (or sealed) and dated on all pages by the investigator or subinvestigator. 
 
The investigator or subinvestigator will review ECG results obtained at the study site, and 
determine the clinical significance of all abnormal ECGs. ECG with possibly drug-related or 
clinically relevant abnormal findings of uncertain causality may be repeated. Any abnormal ECGs 
that persist should be followed at the discretion of the investigator or subinvestigator. ECG tracings 
will be signed (or sealed) and dated on all pages by the investigator or subinvestigator. 
 
12.3 Collection and Recording of Adverse Events 
All adverse events must be collected and recorded in the subject’s study records/source documents, 
in accordance with the normal clinical practice of the investigator or subinvestigator, and those 
occurring between initial dosing of the investigational drug and final evaluation in the follow-up 
observation period recorded in the eCRF.  
 
Each adverse event is to be recorded in the eCRF with the following information: event term (using 
the terminology of the CTCAE v4.0-JCOG), duration, severity, seriousness, action taken with the 
investigational drug/Pem/CDDP, event outcome, and causal relationship to the study treatment, as 
well as DLT (in Phase 1 part only). Definitions are provided below for severity, action taken with 
the investigational drug/Pem/CDDP, event outcome, and causal relationship to the study treatment, 


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as well as DLT evaluation.  
Severity of an adverse event:  
The severity will be graded according to the CTCAE v4.0-JCOG, and the highest grade 
during the course of the event will be recorded. Events not listed in the CTCAE v4.0-JCOG 
will be classified as “- Other (Specify)” at the bottom of the relevant category and graded.  
 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on this general guideline:  
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLNote 1).  
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADLNote2).  
Grade 4: Life-threatening consequences; urgent intervention indicated.  
Grade 5: Death related to AE. 
 
Note 1) Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
Note 2) Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
Action taken with the investigational drug due to the adverse event:  
- Drug Interrupted: BBI608 stopped temporarily.  
- Dose Reduced: BBI608 dose reduced.  
- Drug Withdrawn: BBI608 stopped permanently.  
- Dose Not Changed 
- Not Applicable  
 
Action taken with Pem due to the adverse event:  
- Drug Interrupted: Pem stopped temporarily.  
- Dose Reduced: Pem dose reduced.  
- Drug Withdrawn: Pem stopped permanently.  
- Dose Not Changed 
- Not Applicable  
 
Action taken with CDDP due to the adverse event:  


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- Drug Interrupted: CDDP stopped temporarily.  
- Dose Reduced: CDDP dose reduced.  
- Drug Withdrawn: CDDP stopped permanently.  
- Dose Not Changed 
- Not Applicable  
 
Outcome of the adverse event:  
- Recovered/Resolved 
- Recovering/Resolving 
- Not Recovered/Not Resolved 
- Recovered/Resolved with Sequelae 
- Fatal 
- Unknown 
 
Causal relationship of the adverse event to the study treatment:  
 Not related 
- 
Not related: The event occurred with improbable temporal relationship and is 
plausibly related to other drugs or underlying disease.  
- 
Unlikely: 
The 
event 
occurred 
within 
a 
reasonable 
time 
frame 
after 
administration/discontinuation of the study drug, but there is a likely association of 
an intercurrent/underlying medical condition or other drugs. 
 Related 
- 
Possible: The event occurred in a reasonable time after study drug administration, 
but could be related to concurrent drugs or underlying disease. 
- 
Probable: The event occurred in a reasonable time after study drug administration, is 
unlikely to be attributable to concurrent drugs or underlying disease, and there is a 
plausible mechanism to implicate the study drug.  
- 
Definite: The event occurred in a reasonable time after study drug administration 
and cannot be explained by concurrent drugs or underlying disease. The adverse 
event should respond to dechallenge/rechallenge, however, this is not mandatory 
before assigning a definite causality.  
 
DLT evaluation:  
- DLT  
- Non-DLT [For events assessed as “non-DLT” although it is applicable to the “Definition of 
DLT” [Section 10.5.1, P.50], the basis for the assessment should also be recorded in the 
eCRF.] 


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If an adverse event has occurred, the investigator or subinvestigator will conduct follow-up tests 
and investigations in principle until the event resolves. If the investigator or subinvestigator judges 
that no further follow-up tests or investigations are allowed or required for certain plausible reasons, 
for example when the event is likely attributable to the subject’s primary or concurrent disease or 
the subsequent treatment, the follow-up tests and investigations may be terminated after the 
protocol-defined final evaluation in the follow-up observation period.   
 
The responsible medical monitor is the initial contact person for protocol-related questions or 
discussion of adverse events. The contact information for the responsible medical monitor as well 
as other emergency contact information is provided in Table 1 (page 3) of this protocol.  
 
12.4 Immediately Reportable Events
The following medical events must be immediately reported to the sponsor:  
- Serious adverse events 
- Pregnancy 
Emergency contact information can be found in Table 1 (page 3).  
 
 Serious Adverse Events 
If the investigator or subinvestigator becomes aware of a serious adverse event that occurs in a 
study subject between initial dosing of the investigational drug and final evaluation in the follow-up 
observation period, this must be reported immediately to the sponsor. Serious adverse events 
occurring between initial dosing of the investigational drug and final evaluation in the follow-up 
observation period must be recorded in the eCRF, and the data recorded should match that on the 
serious adverse event report form. 
 
Following the end of subject participation in the study, the investigator will spontaneously report 
serious adverse events to the sponsor if assessed to be related (i.e., definitely, probably, or possibly 
related) to the investigational drug. 
 
Serious adverse events will be followed until resolution, loss to follow-up, stabilization of 
condition, or the event is otherwise explained.   
 
When the investigator or subinvestigator becomes aware of a serious adverse event, the investigator 
or subinvestigator will immediately (roughly within 24 hours of becoming aware of the event) 
notify it to the sponsor directly orally or by telephone, fax or other means. The investigator will 
then, roughly within 3 days, complete and submit the serious adverse event report form to the 


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sponsor. As necessary, the sponsor provides the investigators with the blank serious adverse event 
report form used to report serious adverse events. The report form should include the following 
information:  
- The subject’s previous history of any adverse drug reactions, significant personal or familial 
diathesis, history of the present illness and treatment course, details of the adverse event 
including the circumstances of onset, specific symptoms, treatment, and course.  
- For fatal cases, the date of death, cause of death, relationship between the death and the 
adverse event, and autopsy findings (if available)  
 
The investigator will also immediately submit a written report on the serious adverse event to the 
head of the medical institution. In the report, the serious adverse event must be specified whether 
unexpected (i.e., not listed in the current Investigator’s Brochure, or the nature, severity, specificity, 
or outcome is not consistent with the term or description used in the current Investigator’s 
Brochure) or expected. The investigator will provide additional information regarding the reported 
serious adverse events, upon request of the sponsor, the head of the medical institution or the 
Institutional Review Board. Any update to the adverse event term or seriousness must be reported 
to the sponsor.  
 
In accordance with applicable regulations, the sponsor will notify all study sites and investigators 
of adverse events determined to require expedited reporting to the regulatory authorities.   
 
 Pregnancy 
If the investigator or subinvestigator becomes aware of pregnancy of a subject (or female partner of 
a male subject) between initial dosing of the investigational drug and final evaluation in the 
follow-up observation period, this must be reported promptly to the sponsor.  
 
If a subject becomes pregnant (or is suspected to be pregnant) during the course of the study, the 
investigator or subinvestigator will instruct the subject to immediately discontinue taking the study 
drug. Further, the subject (or female partner of male subject) will be instructed to return promptly 
after the first notification of pregnancy to the study site and undergo a pregnancy test for 
confirmation of pregnancy. If positive, the subject will no longer receive any additional study 
medication. All pregnancies will be followed by the sponsor until resolution (i.e., termination 
[voluntary or spontaneous] or birth) with written consent to pregnancy evaluation and follow-up. 
 
When the investigator or subinvestigator becomes aware of pregnancy, the investigator or 
subinvestigator will promptly notify it to the sponsor directly orally or by telephone, fax or other 
means, and then complete and submit the pregnancy report form to the sponsor. The sponsor 


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provides the investigators with the blank pregnancy report form in advance.  
 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the study drug 
may have interfered with the effectiveness of a contraceptive medication or other adverse events 
were detected. 
 
12.5 Data and Safety Monitoring Board 
The Data and Safety Monitoring Board will review safety data according to the written procedures 
prepared separately.  
 
13. TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG 
13.1 Criteria for Study Drug Discontinuation  
Administration of the study drug must be discontinued for any of the following reasons:  
- Subject’s request to withdraw the consent to the study  
- Pregnancy 
- Noncompliance with study treatment   
a) When the percentage of BBI608-treated days has become or is anticipated to become 
< 50% (during the first 23 days and then during every 21 days)  
b) When, on Day 3 of Cycle 1, the subject does not meet the criteria for starting 
administration of Pem and CDDP, and therefore cannot be started on Pem or CDDP.  
 
If a subject requests to withdraw from the study, the investigator or subinvestigator will ask the 
patient’s willingness about continued participation in the patient outcome investigation, and 
document the result in the medical record etc.  
 
The date of discontinuation (or decision of discontinuation) and reason for discontinuation will be 
recorded in the eCRF.  
 
Administration of the study drug may be discontinued for any of the following reasons. If, in the 
opinion of the investigator or subinvestigator, the subject may no longer safely participate due to a 
change in medical status, administration of the study drug must be discontinued.  
- Adverse events 
- Worsening of the primary disease  
- Lost to follow-up  
- Protocol deviation  
- Other  


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13.2 Criteria for Subject Withdrawal from Patient Outcome Investigation  
Subjects may be withdrawn from patient outcome investigation for any of the following reasons:   
- Lost to follow-up  
- Subject’s request to withdraw the consent to patient outcome investigation  
- Other  
If a subject requests to withdraw from patient outcome investigation, at any time in the study period, 
the investigator or subinvestigator must discontinue patient outcome investigation on the subject.  
 
13.3 Clinical Assessments After Protocol Treatment Discontinuation  
For all treated subjects prematurely discontinuing protocol treatment, regardless of the reason for 
discontinuation, every effort should be made to perform tests at discontinuation shown in Table 2 
(page 10) or Table 5 (page 16). If protocol treatment is discontinued because of other reason than 
imaging-documented worsening, imaging and respiratory function tests will be continued according 
to Table 3 (P.13) even after discontinuation of protocol treatment until worsening is judged by an 
imaging test. If subsequent treatment is started before the judgment of worsening by an imaging 
test, imaging and respiratory function tests will be performed before subsequent treatment as far as 
possible, and no further imaging and respiratory function tests is required after initiation of 
subsequent treatment.  
 
For subjects discontinuing study visits, the investigator or subinvestigator will make every effort to 
determine the reason for discontinuing study visits and the clinical course after the last visit 
(including any onset of adverse events).  
 
For subjects with confirmed willingness about continued participation in the patient outcome 
investigation, even after discontinuation of protocol treatment at the subject’s request, patient 
outcome investigation will be performed according to Table 2 (page 10) or Table 5 (page 16).  
 
14. STUDY TERMINATION 
The sponsor reserves the right to discontinue the study at certain study sites for safety or 
administrative reasons at any time (e.g., serious or continued violation of or deviation from the 
Ministerial Ordinance on GCP or relevant regulatory notifications, this protocol, or study contract 
that affected proper conduct of this study). The sponsor also may suspend or discontinue the study 
when any new finding regarding the quality, efficacy or safety of the investigational drug becomes 
available that could significantly affect continuation of the study. If the sponsor suspends or 
discontinue the study, the sponsor will notify it in writing to the head of the medical institution. The 
head of the medical institution will then notify it in writing to the investigators and the Institutional 


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Review Board.  
 
If the investigator decides to suspend or discontinue the study at the study site, the investigator will 
promptly notify it along with the reasons in writing to the head of the medical institution. The head 
of the medical institution will then notify it in writing to the Institutional Review Board and the 
sponsor.  
 
If the study is terminated and/or the study site is closed for whatever reason, all study medications 
pertaining to the study must be returned to the sponsor. The investigator should promptly notify the 
subjects about study termination, and provide the subjects with appropriate treatment and take other 
necessary actions.  
 
15. STATISTICS 
Detailed methods of statistical analyses are specified in the statistical analysis plan. The sponsor 
will finalize the statistical analysis plan before the study database lock. The sponsor will also 
determine the specific handling of data, such as inclusion/exclusion for analysis sets, before the 
data lock.  
 
15.1 Sample Size Determination  
Phase 1 part: 3 to 6 subjects evaluable for DLT  
Phase 2 part: 20 subjects given protocol treatment at least once, including 15 subjects with 
epithelioid histology.  
 
Rationale for sample size:  
Phase 1 part: In line with the 3 + 3 design, the sample size is set at 3 with a maximum of 6 as the 
number required for determination of the safety of BBI608 combined with Pem plus 
CDDP.  
Phase 2 part: The sample size is set at 20 as the number required and feasible to explore the 
efficacy of BBI608 combined with Pem plus CDDP in patients with MPM. A 
sample size of 20 will allow observation (detection) of at least one case of adverse 
events occurring at an incidence of 10% with a ≥ 80% power. With Pem plus CDDP 
combination therapy, the 6-month PFS rate can be approximately 30–35% based on 
a phase 1/2 study of Pem plus CDDP in MPM patients in Japan that reported a 
median PFS of 4.7 months6); thus, this study needs to yield a 6-month PFS rate of 
≥ 30% to demonstrate noninferiority of the protocol treatment with add-on BBI608 
for the target disease. Given that an overseas study of add-on bevacizumab to Pem 
plus CDDP reported a 6-month PFS rate of 56%25), the 6-month PFS rate with 


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add-on BBI608 to Pem plus CDDP may be assumed to be 60%. If the efficacy is 
measured by the 6-month PFS rate, with a threshold value of 30% and an expected 
value of 60%, a sample size of 20 with a two-sided significance level of 10% will 
yield 87.2% power.  
 
15.2 Analysis Populations  
 Safety Analysis Population  
All subjects who received the investigational drug.  
 
 DLT Evaluation Population  
Subjects who received the investigational drug in Phase 1 part and met either of the following:  
- Subjects with a ≥ 80% BBI608 treatment compliance rate during the DLT evaluation period, 
as calculated by the following formula:  
[Amount of BBI608 actually taken/(Protocol-specified dose* × 45)] × 100 (%) 
*Protocol-specified dose = 480 mg 
- Subjects with onset of DLT during the DLT evaluation period  
 
 Pharmacokinetics Population  
The pharmacokinetics population will consist of subjects who received BBI608 with the post-dose 
plasma BBI608 concentration data available for at least one time point.  
 
 Efficacy Analysis Population (Modified Intention-to-Treat Population)  
Subjects who received the investigational drug 
 
15.3 Data Analysis  
 Subject Disposition  
The following will be summarized for the entire study and separately for Phase 1 part and Phase 2 
part: number of patients enrolled, number of subjects given no dose of the investigational drug, 
number of treated subjects, number of subjects completing the DLT evaluation period (Phase 1 part 
only), and number of subjects who discontinued study treatment.   
 
 Drug Exposure and Compliance  
In the safety and efficacy analysis sets, and separately for Phase 1 part and Phase 2 part, summary 
statistics will be calculated for the duration of treatment with the investigational drug, total 
cumulative dose, and treatment compliance rate.  
 


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 Important Protocol Deviations  
Important Protocol Deviations (IPDs) will be identified and documented based on a review of 
potentially IPDs. The potentially IPDs to be reviewed include, but are not limited to, subjects who: 
- Did not fulfill the inclusion criteria or met any of the exclusion criteria. 
- Used any prohibited concomitant medications or therapies. 
 
Individual IPDs will be presented in a data listing. The number and percentage of subjects with 
IPDs will be summarized by type of deviation. 
 
 Demographic and Other Baseline Characteristics 
In each analysis set, and separately for Phase 1 part and Phase 2 part, summary statistics will be 
calculated for demographic and other baseline characteristics.  
 
 
 Efficacy Analysis 
Efficacy will be analyzed using the efficacy analysis population (i.e., modified ITT population), 
separately for Phase 1 part and Phase 2 part (including patients with MPM in Phase 1 part).  
 
PFS is defined as the time from BBI608 administration to documented PD (as assessed according 
to the mRECIST or RECIST 1.1) or death, whichever is earlier. For imaging in Phase 2 part, the 
result by the imaging assessment committee will be used. Subjects with neither PD nor death will 
be censored at their last evaluation for tumor response. Patients who have not received any imaging 
test after starting the investigational drug administration will be censored on the day of first dose of 
investigational drug administration except for cases of death before the planned initial imaging test 
(in case of death before the initial imaging test, death will be handled as 1 event). Patients who 
have started a new subsequent treatment (chemotherapy, radiotherapy, hormonal therapy, 
immunotherapy, thermotherapy, or surgical therapy) before exacerbation observed will be censored 
on the date of imaging test that has lastly recorded no exacerbation observed before starting the 
new subsequent treatment. 
 
OS is defined as the time from BBI608 administration to death from any cause. Subjects alive at 
final observation or lost to follow-up will be censored at their last contact (i.e., visit or telephone) 
date.  
 
15.3.5.1 Phase 1 Part Efficacy Analysis  
Data from MPM patients and NSCLC patients will be combined for efficacy analysis.  
 
The best overall response of CR, PR, SD, PD, or NE according to the RECIST 1.1 or mRECIST 


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will be summarized in frequency tables.  
 
For PFS and OS, the Kaplan-Meier curves will be plotted. The median PFS and median OS will be 
calculated.  
 
Summary statistics of measurement values and changes from baseline at each evaluation time point 
will be calculated for respiratory function tests (VC, FVC, FEV1). 
 
15.3.5.2 Phase 2 Part Efficacy Analysis  
The efficacy data from MPM patients in Phase 1 part will be included in the Phase 2 part efficacy 
analysis.  
 
15.3.5.2.1 Primary Endpoints  
For PFS, the Kaplan-Meier curve will be plotted, and the median PFS will be calculated. In 
addition, the 6-month PFS rate will be calculated.   
 
15.3.5.2.2 Secondary Endpoints  
- For OS, the Kaplan-Meier curve will be plotted, and the median OS will be calculated.   
- The best overall response of CR, PR, SD, PD, or NE according to the RECIST 1.1 or 
mRECIST will be summarized in frequency tables. In addition, the RR and DCR will be 
calculated.  
- In terms of respiratory function tests (i.e., VC, FVC, and FEV1) at each time of evaluation, 
summary statistics will be calculated for observed values and change from baseline.  
 
15.3.5.3 Adjustment for Multiplicity  
Since no statistical test will be performed, the level of significance is not set.  
 
15.3.5.4 Subgroup Analysis  
For PFS, OS, tumor response, and respiratory function tests (VC, FVC, FEV1), subgroup analyses 
will be performed according to histological type of mesothelioma (epithelioid, sarcomatoid, 
biphasic) or number of treatment cycles. 
 
 Safety Analysis  
Safety will be analyzed using the safety analysis population, and the data will be summarized for 
the entire study and separately for Phase 1 part and Phase 2 part.  
 
The safety data from MPM patients in Phase 1 part will be included in the Phase 2 part safety 


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analysis.  
 
15.3.6.1 Dose Limiting Toxicity (DLT) 
Number of patients with onset of DLT and incidence during the DLT evaluation period will be 
calculated in the DLT evaluation population. 
 
15.3.6.2 Adverse Events 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  
 
Adverse events will be summarized by MedDRA System Organ Class (SOC) and Preferred Term 
(PT). Adverse drug reactions are defined as treatment-related adverse events, i.e., those assessed as 
“Definitely related,” “Probably related,” or “Possibly related” to the investigational drug.  
 
The following adverse events will be summarized by SOC and PT for the safety analysis 
population:   
- All adverse events (number of events, number of subjects, and incidence)  
- Adverse events by grade 
- Adverse events by causal relationship to the investigational drug (adverse events, adverse 
drug reactions)  
- Adverse events by time to onset  
- Adverse events by dose at the time of onset 
 
The following conventions will be followed in summarizing adverse events:  
- For subject incidence summaries, each subject will be counted only once within each SOC 
and within each preferred term.  
-  If a subject reports more than one adverse event within a preferred term and/or a body 
system, the adverse event with the highest known severity within each body system and 
within each preferred term will be included in the summaries by severity.  
 
Listing of fatal adverse events, serious adverse events, and adverse events leading to treatment 
discontinuation will also be presented, as with the listing of all adverse events. 
 
15.3.6.3 Clinical Laboratory Assessments   
The measured values at each time of evaluation will be summarized using summary statistics.  
 


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15.3.6.4 ECG  
The measured values at each time of evaluation will be summarized using summary statistics.  
 
15.3.6.5 Vital Signs  
The measured values at each time of evaluation will be summarized using summary statistics.  
 
15.3.6.6 Subgroup Analyses  
No subgroup analysis will be performed on safety.  
 
 Pharmacokinetic Analysis  
For the pharmacokinetics population, listings of the plasma concentrations of BBI608, Pem and 
CDDP at each time point of blood sampling as well as BBI608 pharmacokinetic parameters will be 
presented. Also, for individual subjects, graphs plotting plasma drug concentration (on the vertical 
axis) versus time (on the horizontal axis) will be constructed.  
 
 Interim Analysis  
No interim analysis is planned.  
 
 Handling of Data 
Individual data will be handled as described below.  
 
15.3.9.1 Data Excluded from Analysis  
No particular restriction is set.  
When certain data need to be excluded from an analysis, the sponsor will discuss at a Data Review 
Meeting (DRM) to decide the handling of the data.   
 
15.3.9.2 Definition of Baseline  
Baseline is defined as the tests results obtained between Day −7 and the start of BBI608 
administration. If multiple measurements are available, the last or later measurement obtained 
during this period will serve as the baseline.  
 
15.3.9.3 Handling of Missing Data  
Missing data will not be imputed.  
 


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16. PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL, DATA 
COLLECTION, DATA MANAGEMENT, AND QUALITY ASSURANCE 
16.1 Data Collection/Electronic Data Capture (EDC)  
This study will use an Electronic Data Capture (EDC) system. For all subjects enrolled in this study, 
eCRF will be completed with the data up to patient outcome investigation.  
 
For the following items, however, the data will be collected as part of study data, but not recorded 
in the eCRF:  
- Biomarker results by the pathological assessment committee  
- Imaging assessment results by the imaging assessment committee 
- Plasma drug concentration measurements  
 
The investigator or subinvestigator will complete the eCRF promptly. The investigator will review 
all eCRFs for individual subjects, and verify the entries in the eCRFs by electronically signing the 
eCRFs.   
 
Clinical research coordinators may be involved in completing eCRFs, provided that the following 
conditions are met:   
1) The clinical research coordinators only transcribe data from source documents.  
2) The investigator has submitted a list of the names of clinical research coordinators and duty 
assignments to the head of the medical institution in advance, and obtained his/her approval.  
The sponsor will obtain the original eCRFs electronically signed by the investigator, while the 
investigator will retain a copy of the eCRFs. For any inconsistencies between the eCRF and source 
documents, the investigator will prepare a record explaining the reasons and submit it to the 
sponsor, while retaining a copy of the record.  
 
Any changes or corrections to the eCRF will be made according to the written instructions provided 
by the sponsor.  
 
For the following data among other data in the eCRF, the eCRFs may be regarded as source 
documents:   
1) Route of administration and reason for use of concomitant drugs, reason for use of 
concomitant therapies  
2) Lesion findings: target lesions (organs, specific sites of lesions, size), non-target lesions 
(presence or absence, organs), new lesions (site), tumor response assessment  
3) Adverse event severity and seriousness 
4) Assessment of causal relationship between adverse events and the investigational drug 


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5) Adverse event outcome and date of outcome  
6) DLT evaluation 
7) 12-lead ECG normal/abnormal assessment (specific abnormal findings if any)  
8) Chest X-ray normal/abnormal assessment (specific abnormal findings if any)   
9) Reason for discontinuation of administration of the investigational drug 
10) Best overall response of tumors  
 
16.2 Study Monitoring  
This study will be monitored from initiation to completion by the sponsor. Monitoring will include 
personal visits and telephone communication to assure that the study is conducted in compliance 
with the protocol, GCP Ordinance and relevant regulatory notifications. On-site reviews of eCRFs 
will include a review of forms for completeness and clarity, and consistency with source documents 
available for each subject. 
 
16.3 Audits  
This study is subject to audits by the sponsor’s auditor at the sponsor or study sites as needed. If 
such an audit occurs, the investigator will agree to allow access to required subject records. This is 
dependent on the subject granting consent by signing the informed consent form, which will be 
explained to subjects. By signing this protocol, the investigator grants permission to personnel from 
the sponsor for on-site auditing (of study-related documents and procedures employed in eCRF 
generation).  
16.4 Study Documentation  
Study records are comprised of source documents, eCRF and all other administrative documents. 
Source document is defined as any handwritten, computer generated output, or electronically 
recorded data that contain medical information or test results that have been collected for or are in 
support of the protocol specifications.  
 
16.5 Clinical Laboratory Certification and Normal Values  
A site laboratory will be used for laboratory tests for this study. The study site will provide the 
sponsor with laboratory certification or its copy, and a dated list of current normal range values for 
the site laboratory.  
 
17. ETHICAL AND REGULATORY OBLIGATIONS 
17.1 Ethical Conduct of the Study and GCP Compliance  
The investigator agrees that the study will be conducted in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki, protocol, “Act on Securing Quality, Efficacy 
and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, 


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Gene Therapy Products, and Cosmetics”,, GCP Ordinance and relevant regulatory notifications, 
and ICH guidelines. The investigator will conduct all aspects of the study in accordance with 
applicable local laws and regulations. 
 
The investigator will assure proper implementation and conduct of the study, including 
study-related duties delegated to other appropriately qualified individuals. The investigator will 
assure that study staff cooperate with monitoring and audits. The investigator will sign (or seal with 
name) and return the “Investigator Approval” page to the sponsor. 
 
17.2 Institutional Review Board  
In accordance with GCP Ordinance and relevant regulatory notifications, the head of the medical 
institution will obtain documented approval for conducting the study from appropriate Institutional 
Review Board (IRB) prior to initiation of the study, and forward it to the sponsor. When necessary, 
an amendment or renewal of the IRB approval must be obtained and also forwarded to the sponsor. 
The IRB must supply the sponsor a list of the IRB members, and a statement to confirm that the 
IRB is organized and operates according to GCP Ordinance and relevant regulatory notifications. 
 
A copy of written IRB approval or favorable opinion of the protocol, informed consent form and 
subject recruitment material (if applicable) must be provided to the sponsor prior to start of the 
study. The approval or favorable opinion letter must be signed by the IRB chairperson or designee, 
identify the IRB name and address, identify the clinical protocol by title and/or protocol number, 
and include the date that approval was granted. The IRB will conduct a continued review of the 
clinical study at intervals not to exceed one year or when judged to be required by the head of the 
medical institution. The sponsor must be supplied with written documentation of continued review 
of the clinical study.  
 
17.3 Informed Consent  
The investigator will prepare the informed consent form and provide the form to sponsor for 
approval prior to submission to the IRB. The sponsor may provide a template informed consent 
form. The informed consent form must contain the elements required by GCP Ordinance and 
relevant regulatory notifications, and will be subject to sponsor approval as well as IRB approval.  
 
Before recruitment and enrollment, each prospective subject will be given a full explanation of the 
study from the investigator or subinvestigator, allowed to read the approved informed consent form 
and be provided ample time and the opportunity to ask any questions that may arise. Once all 
questions have been answered and the investigator or subinvestigator is assured that the prospective 
subject understands the implications of participating in the study, the prospective subject will be 


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asked to give consent to participate in the study by signing the informed consent form. As part of 
the consent process, each prospective subject must consent to direct access to his/her medical 
records for study-related monitoring, auditing, IRB review, and Japanese/overseas regulatory 
inspection. It should be clearly explained to each prospective subject that participation in each and 
every clinical visit and assessment is expected. The subject may be discontinued from study 
treatment, but that does not necessarily negate the expectation that the subject will continue to 
participate in the study through the final visit/assessment and patient outcome investigation. The 
investigator or subinvestigator will provide a copy of the signed informed consent form to each 
subject, and will record the date of the informed consent in the eCRF.  
 
Signed and dated consent of the subject must be obtained by the investigator or subinvestigator 
prior to any procedure or test for the study (e.g., collection of blood or other specimens, lifestyle 
restrictions, physical examination). Only in Phase 1 part, if treatment is continued to Cycle ≥ 2 in 
the subject, signed and dated voluntary re-consent of the subject must be obtained by the 
investigator or subinvestigator between Day 17 of Cycle 1 and the start of Cycle 2 therapy.  
 
If the prospective subject is receiving treatment from another physician, the investigator or 
subinvestigator will contact the other physician with agreement of the prospective subject to notify 
about his/her participation in the study.  
 
If an amendment to the protocol changes the subject participation schedule in scope or activity, or if 
important new information becomes available that may be relevant to the subject’s consent, this 
must be notified to the subject and documented, and the informed consent form must be revised and 
submitted to the IRB for review and approval or favorable opinion. The revised informed consent 
form must be used to obtain re-consent from a subject currently enrolled in the study if he or she is 
affected by the amendment. The revised informed consent form must be used to obtain consent 
from any new subjects who are enrolled into the study after the date of the approval or favorable 
opinion of the protocol amendment. 
 
17.4 Subject Privacy  
The sponsor affirms the subjects’ confidentiality. The subjects will be identified by unique codes; 
subjects’ names will be masked prior to transmission to the sponsor. The confidentiality of the 
subject’s personal data shall be protected in accordance with appropriate local laws and regulations. 
 
Subjects’ privacy will be protected also in any publication of study results.  
 


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17.5 Protocol Amendments and Emergency Deviations 
For any revisions and/or amendments to this protocol, the investigator must obtain written approval 
from the sponsor and the IRB. The investigator will not make any changes to the conduct of the 
study or the protocol without first obtaining written approval from the sponsor and the IRB, except 
where necessary to eliminate an apparent immediate hazard to a study subject. Emergency 
deviations or modifications may be initiated without sponsor or IRB approval, only in cases where 
the deviation or modification is necessary to eliminate or avoid an immediate apparent hazard to 
subjects. Emergency deviations or modifications must be immediately reported to the sponsor and 
the head of the medical institution, as well as the IRB via the head of the medical institution. In 
such instances, the investigator will submit a report of the specific deviation or modification and 
the reasons, and if necessary a draft protocol amendment, as promptly as possible to the sponsor 
and the head of the medical institution, as well as the IRB via the head of the medical institution. In 
addition, the investigator will obtain written approval from the head of the medical institution and 
from the sponsor via the head of the medical institution.    
 
The investigator or subinvestigator will record all deviations. For emergency deviations to avoid an 
immediate hazard to subjects or for other unavoidable medical reasons, the investigator will prepare 
the record explaining the reasons and immediately submit it to the head of the medical institution 
and sponsor, while retaining its copy. 
 
The sponsor may amend the protocol as necessary. Amendments will be discussed with and agreed 
upon by the investigators, and approved by the IRB, with the exception of administrative changes 
for which the sponsor will make necessary amendments to the protocol.  
 
17.6 Records Retention  
The head of the medical institution and the founder of the IRB will retain all study-related 
documents that need to be retained at the site in accordance with GCP Ordinance and relevant 
regulatory notifications, for at least 15 years from time of participation in the study or until 1) or 2) 
below, whichever is longer.  
1) Market approval for the investigational drug (If the clinical development is discontinued, 3 
years after the date of receipt of the notice that the clinical development is discontinued.)  
The sponsor will notify the medical institutions and IRBs when the market approval is 
granted or the clinical development is discontinued.  
2) Three years after discontinuation or completion of the study.  
 
The head of the medical institution and the founder of the IRB should take measures to prevent 
accidental or premature destruction of these documents. Documents cannot be destroyed without 


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written sponsor authorization. The sponsor will inform the medical institutions and IRBs when the 
destruction of documents is permitted. 
 
17.7 Inspection of Records by Regulatory Agencies  
In the event of an inspection by Japanese or overseas regulatory agencies, the head of the medical 
institution and investigator agree to allow representatives of the sponsor and regulatory authorities 
to have access to all study records, and cooperate in the inspection. The medical institution or 
investigator will promptly notify the sponsor of all requests to inspect the study by regulatory 
agencies and will promptly forward a copy of all such inspection reports. 
 
17.8 Publication Policy  
Any formal presentation or publication of data collected as a direct or indirect result of the study 
will be considered a joint publication by the principle coordinating investigator or the investigator 
and the sponsor. For multicenter studies, it is mandatory that the first publication is based on all 
data obtained from all analyses as stipulated in the protocol. Investigators participating in 
multicenter studies must agree not to present data gathered individually or by a subgroup of centers 
before the full, initial publication. 
 
17.9 Compensation  
1) In the event of study-related injury to subjects, the sponsor will compensate for it according 
to the compensation system established by the sponsor, even if the sponsor is not liable for 
the injury, with the exception of “a)” to “d)” below:  
a) No compensation will be paid when the health injury was causally unrelated to the study.   
b) No compensation will be paid when the health injury was caused by an act for which the 
medical institution or a third party is liable.  
c) No compensation will be paid for lack of expected pharmacological or other benefits.   
d) No or reduced compensation may be paid when the health injury is caused by an 
intentional act or serious negligence of the subject.  
2) The sponsor will take appropriate measures for possible compensation, such as buying an 
insurance policy.  
 
17.10 
Payment of Transportation Fees and Other Expenses Associated with 
Participation in the Study to Reduce Financial Burdens on Subjects 
To reduce burdens entailed in study participation, subjects may be paid money to cover 
transportation fees and other expenses in accordance with the rules of the medical institution.  
 


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18. REFERENCES 
1) Annual trend in deaths from mesothelioma (from 1995 to 2013) by prefecture and for 21 
major cities (regrouped). Ministry of Health, Labour and Welfare Vital Statistics 2013.  
2) Takashi Nakano. Mesothelioma: Reason for increase and perspective. Consensus of Cancer 
Ther. 2005; 4: 222-4. 
3) Murayama T, Takahashi K, Natori Y, Kurumatani N. Estimation of future mortality from 
pleural malignant mesothelioma in Japan based on an age-cohort model. Am J Ind Med. 
2006; 49: 1-7. 
4) National Comprehensive Cancer Network (NCCN) (US). NCCN clinical practice guidelines 
in oncology (NCCN Guidelines). Malignant Pleural Mesothelioma. Ver. 1. 2014. 
5) Vogelzang NJ, Rusthoven JJ, Denham C, Pierre Ruffie EK, Gatzemeier U, Boyer M, Emri S, 
et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in 
patients with malignant pleural mesothelioma. J Clin Oncol. 2003; 21 (14): 2636-44. 
6) Nakagawa K, Yamazaki K, Kunitoh H, Hida T, Gemba K, Shinkai T, et al. Efficacy and 
safety of pemetrexed in combination with cisplatin for malignant pleural mesothelioma: a 
phase I/II study in Japanese patients. Jpn J Clin Oncol. 2008; 38(5): 339-46. 
7) 17 articles on cancer stem cells in J Clin Oncol. 2008; 26(17). 
8) Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that 
originates from a primitive hematopoietic cell. Nat Med. 1997; 3: 730-7. 
9) Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective 
identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003; 100: 
3983-8. 
10) Lobo NA, Shimono Y, Qian D, Clarke MF. The Biology of Cancer Stem Cells. Annu Rev 
Cell Dev Biol. 2007; 23: 675-99. 
11) Varghese S, Whipple R, Martin SS, Alexander HR. Multipotent cancer stem cells derived 
from human malignant peritoneal mesothelioma promote tumorigenesis. PLoS One. 2012; 
7: e52825. 
12) Adachi Y, Aoki C, Yoshio-Hoshino N, Takayama K, Curiel DT, Nishimoto N. Interleukin-6 
induces both cell growth and VEGF production in malignant mesotheliomas. Int J Cancer. 
2006 Sep 15; 119(6): 1303-11. 
13) Achcar Rde O, Cagle PT, Jagirdar J. Expression of activated and latent signal transducer 
and activator of transcription 3 in 303 non-small cell lung carcinomas and 44 malignant 
mesotheliomas: possible role for chemotherapeutic intervention. Arch Pathol Lab Med. 
2007 Sep; 131 (9): 1350-60. 
14) Darnell JE. Validating Stat3 in cancer therapy. Nat Med. 2005; 11 (6): 595-6. 
15) Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, et al. Activation of 
STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep. 2006; 15: 


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1445-51. 
16) Jackson CB, Giraud AS. STAT3 as a prognostic marker in human gastric cancer. J 
Gastroenterol Hepatol. 2009; 24: 505-7. 
17) Shah NG, Trivedi TI, Tankshali RA, Goswami JV, Jetly DH, Shukla SN, et al. Prognostic 
significance of molecular markers in oral squamous cell carcinoma: a multivariate analysis. 
Head Neck. 2009; 31: 1544-56. 
18) Sheen-Chen SM, Huang CC, Tang RP, Chou FF, Eng HL. Prognostic value of signal 
transducers and activators of transcription 3 in breast cancer. Cancer Epidemiol Biomarkers 
Prev. 2008; 17: 2286-90. 
19) Rosen DG, Mercado-Uribe I, Yang G, Bast RC Jr, Amin HM, Lai R, et al. The role of 
constitutively active signal transducer and activator of transcription 3 in ovarian 
tumorigenesis and prognosis. Cancer. 2006; 107: 2730-40. 
20) Alimta® Drug Interview Form. Eli Lilly Japan K.K. 2014 Jan (9th version)  
21) IA-Call® Regulatory Review Report. Nippon Kayaku Co., Ltd. 2003 Nov 6.  
22) Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med. 2005. Oct 
13; 353 (15): 1591-603. 
23) Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et.al. PARAMOUNT: 
Final overall survival results of the phase III study of maintenance pemetrexed versus 
placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced 
nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10; 31 (23): 2895-902.  
24) Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant 
pleural mesothelioma. Ann Oncol. 2004 Feb; 15(2): 257-60. 
25) Dowell JE, Dunphy FR, Taub RN, Gerber DE, Ngov L, Yan J, et al. A multicenter phase II 
study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant 
mesothelioma. Lung Cancer. 2012 Sep; 77(3): 567-71. 
 
19. APPENDIX 
APPENDIX I. Study Contacts 
- Study Administrative Organization (List of Study Sites and Investigators) (in separate issues)  
- Study Administrative Organization (Other) (Attachment)  
 

SAP_001.pdf: 
Official title: A Phase I/II Clinical Study of BBI608 in Combination With Pemetrexed and Cisplatin 
in Adult Patients With Malignant Pleural Mesothelioma 
NCT number: NCT02347917 
Document date: 2018/1/18 




Statistical Analysis Plan 
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Version Date: January 18, 2018 
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Version History 
 
Version 
Author 
Approval date 
Approver 
Reason of changes 
1 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
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Version Date: January 18, 2018 
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Content 
 
1. Introduction................................................................................................................. 6 
2. List of abbreviations and definitions of terms ............................................................ 6 
3. Change from analyses planned in the protocol ........................................................... 7 
4. Study synopsis ............................................................................................................ 7 
4.1 
Study design ........................................................................................................ 7 
4.2 
Objectives ............................................................................................................ 7 
4.2.1 
Phase 1 part .................................................................................................. 7 
4.2.2 
Phase 2 part .................................................................................................. 8 
4.3 
Protocol treat ....................................................................................................... 8 
4.4 
Protocol period .................................................................................................... 8 
4.4.1 
Treatment period .......................................................................................... 8 
4.4.2 
DLT evaluation period ................................................................................. 9 
4.4.3 
Follow-up observation period ...................................................................... 9 
4.4.4 
Patient outcome investigation ...................................................................... 9 
4.5 
Schedule of assessments ...................................................................................... 9 
4.6 
Determination of sample size ............................................................................ 18 
5. Analysis population .................................................................................................. 18 
5.1 
Safety analysis population ................................................................................. 18 
5.2 
DLT evaluable population ................................................................................. 18 
5.3 
Pharmacokinetics analysis population............................................................... 18 
5.4 
Efficacy analysis population (modified ITT population: mITT population) ..... 18 
6. Safety and efficacy endpoints ................................................................................... 18 
6.1 
Phase 1 part ....................................................................................................... 18 
6.1.1 
Safety endpoints ......................................................................................... 18 
6.1.2 
Efficacy endpoints ..................................................................................... 19 
6.1.3 
Pharmacokinetic endpoints ........................................................................ 19 
6.2 
Phase 2 part ....................................................................................................... 19 
6.2.1 
Efficacy endpoints ..................................................................................... 19 
6.2.2 
Safety endpoints ......................................................................................... 20 
6.2.3 
Other endpoints .......................................................................................... 20 
7. General data handling ............................................................................................... 20 
7.1 
Definition and data handling ............................................................................. 20 
7.1.1 
Data excluded from the analyses ............................................................... 20 


Statistical Analysis Plan 
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Version Date: January 18, 2018 
Page 4 of 37 
7.1.2 
Definition of visit ....................................................................................... 21 
7.1.3 
Handling of missing data ........................................................................... 22 
7.1.4 
Prior and Concomitant medications ........................................................... 22 
7.2 
Statistical methodology ..................................................................................... 22 
7.2.1 
Software ..................................................................................................... 22 
7.2.2 
Summary statistics ..................................................................................... 23 
7.2.3 
Significant level and p value, confidential interval ................................... 23 
7.2.4 
Multiple comparison/Multiplicity .............................................................. 23 
7.2.5 
Definition of terms ..................................................................................... 23 
8. Analysis of subjects .................................................................................................. 24 
8.1 
Disposition of subjects ...................................................................................... 24 
8.2 
Important Protocol Deviation ............................................................................ 24 
8.3 
Analysis population ........................................................................................... 24 
8.4 
Demographic and other baseline characteristics ............................................... 25 
8.5 
Measurements of treatment compliance ............................................................ 25 
8.5.1 
Treatment compliance and intensity .......................................................... 25 
8.5.2 
Duration of exposure ................................................................................. 26 
8.5.3 
Cumulative dose ........................................................................................ 26 
8.5.4 
Mean daily dose ......................................................................................... 26 
8.5.5 
Modal daily dose ........................................................................................ 26 
8.6 
Prior and Concomitant medications .................................................................. 27 
9. Analysis of efficacy assessment ............................................................................... 27 
9.1 
Definition of efficacy endpoint ......................................................................... 27 
9.1.1 
Progression Free Survival (PFS) ................................................................ 27 
9.1.2 
Overall Survival (OS) ................................................................................ 30 
9.1.3 
Response Rate (RR) ................................................................................... 30 
9.1.4 
Disease Control Rate (DCR) ...................................................................... 30 
9.1.5 
Duration of response .................................................................................. 30 
9.1.6 
Duration of disease control ........................................................................ 30 
9.2 
Phase 1 part ....................................................................................................... 30 
9.2.1 
Tumor response .......................................................................................... 30 
9.2.2 
Progression Free Survival (PFS) ................................................................ 30 
9.2.3 
Overall Survival (OS) ................................................................................ 30 
9.2.4 
Respiratory Function Tests ........................................................................ 31 
9.3 
Phase 2 part ....................................................................................................... 31 
9.3.1 
Primary endpoints ...................................................................................... 31 


Statistical Analysis Plan 
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9.3.2 
Secondary endpoints .................................................................................. 31 
9.3.3 
Subgroup analysis ...................................................................................... 31 
10. Analysis of Safety assessment .................................................................................. 32 
10.1 Adverse Events .................................................................................................. 32 
10.1.1 
Overall summary of AEs ............................................................................ 32 
10.1.2 
Summary of AE by MedDRA .................................................................... 32 
10.1.3 
Summary of AE by onset ........................................................................... 32 
10.1.4 
Summary of AE by first onset .................................................................... 33 
10.2 DLT evaluation .................................................................................................. 33 
10.3 Clinical laboratory evaluation ........................................................................... 33 
10.3.1 
Summary of hematology and biochemistry ............................................... 33 
10.3.2 
Summary of urinalysis ............................................................................... 33 
10.3.3 
Summary of CTCAE grade ........................................................................ 33 
10.3.4 
Potential Clinical Significant ..................................................................... 34 
10.4 Vital signs and Body weight evaluation ............................................................ 34 
10.5 12-lead ECG evaluation .................................................................................... 34 
10.6 ECOG PS evaluation ......................................................................................... 34 
10.7 Chest X-ray evaluation ...................................................................................... 34 
11. Analysis of Pharmacokinetics assessment ................................................................ 34 
11.1 Handling of data ................................................................................................ 34 
11.1.1 
Reporting conventions ............................................................................... 35 
11.2 Method of PK parameter estimation ................................................................. 35 
12. Clinical significant laboratory abnormalities............................................................ 36 
 
 
 


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1. Introduction 
This statistical analysis plan (SAP) describes the rules and convention to be used in the 
presentation and analysis for study D8807005. It describes, in detail, the data and 
variables to be summarized and analyzed, including specifics of the statistical analyses 
to be performed. This analysis plan is based on the protocol with Amendment 3.02 
dated 12 September 2017. 
 
 
2. List of abbreviations and definitions of terms 
Abbreviation 
Term 
95％CI 
95% confidential interval 
ADR 
adverse drug reaction 
AE 
adverse event 
AUC 
area under the concentration-time curve 
BLQ 
below limit of quantitation 
CDDP 
cisplatin 
Cmax 
maximum drug concentration 
Cmin 
minimum drug concentration 
CR 
complete response 
DCR 
disease control rate 
DLT 
dose limited toxicity 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
LLOQ 
lower limit of quantification 
Max 
maximum 
Min 
minimum 
MPM 
Malignant pleural mesothelioma 
MRT 
mean residence time 
MST 
median survival time 
NCI CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NE 
not evaluable 
NSCLC 
Non-small cell lung cancer 
OS 
overall survival 
PD 
progressive disease 
Pem 
Pemetrexed 
PFS 
progression free survival 


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PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
stable disease 
SD 
standard deviation 
t1/2 
terminal elimination half-life 
tmax 
time to reach maximum plasma concentration 
ULOQ 
upper limit of quantification 
WHO-DD 
WHO Drug Dictionary 
λz 
terminal elimination rate constant  
 
 
3. Change from analyses planned in the protocol 
Following analyses valuables are added to analysis plan in the protocol. 
- 
Treatment compliance and intensity 
- 
One-year overall survival rate 
- 
Duration of response and disease control 
- 
H-Score and Total percent positive as biomarker analysis 
- 
Adverse event by first onset 
- 
ECOG PS 
For efficacy analysis, the subgroup analysis by treatment duration is removed from 
analysis plan in the protocol. 
 
4. Study synopsis 
4.1 
Study design 
This study consists of Phase 1 part and Phase 2 part, both using a multicenter, 
open-label, uncontrolled design. The study will proceed to Phase 2 part only after 
Phase 1 part demonstrates the tolerability of BBI608 in combination with Pemetrexed 
(Pem) plus cisplatin (CDDP) based on complete assessment of dose limiting toxicity 
(DLT) (with occurrence of DLT in no or 1 of 6 subjects). 
 
4.2 
Objectives 
4.2.1 
Phase 1 part 
Primary objective 
To evaluate the safety, tolerability and pharmacokinetics of BBI608 combined with 
Pem plus CDDP in patients with malignant pleural mesothelioma (MPM) or non-small 
cell lung cancer (NSCLC). 


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Secondary objective 
To evaluate the efficacy of BBI608 combined with Pem plus CDDP. 
 
4.2.2 
Phase 2 part 
Primary objective 
To evaluate the efficacy and safety of BBI608 combined with Pem plus CDDP in 
patients with MPM. 
 
Secondary objective 
To explore biomarkers related to the efficacy of BBI608. 
 
4.3 
Protocol treat 
(1) BBI608 
BBI608 will be orally administrated at a dose of 480 mg twice daily (morning and 
evening) (daily dose, 960 mg). Each dose will be taken at either 1 hour before or 2 
hours after a meal, with dosing intervals of approximately 12 hours. On Day 1 of Phase 
1 part, however, only the morning dose will be administrated. 
 
(2) Pemetrexed (Pem) 
Pem, as a marketed product, will be intravenously administered at 500 mg/m2 by drip 
infusion over 10 minutes on Day 1 of each treatment cycle (except for Cycle 1, in 
which Pem will be given on Day 3). Each infusion of Pem will start ≥4 hours after a 
dose of BBI608. Premeditation with folic acid and vitamin B12 should be given to 
reduce occurrence of serious adverse drug reactions, with reference to the package 
insert for Pem. 
 
(3) Cisplatin (CDDP) 
CDDP, as a marketed product, will be intravenously administered at 75 mg/m2 by drip 
infusion over ≥2 hours. Each infusion of CDDP will start at 30 to 50 minutes after a 
dose of Pem. To reduce nephrotoxicity of CDDP, fluid infusion, diuretic therapy, and 
other treatments should be given, with reference to the package insert for CDDP. 
 
4.4 
Protocol period 
4.4.1 
Treatment period 
Each cycle consists of 21 days (with the exception of cycle 1 which consists of 23 
days). No restriction is set on the number of cycles. Administration of BBI608 will be 


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started within 14 days after enrollment. 
 
4.4.2 
DLT evaluation period 
The DLT evaluation period is defined as the period following administration of 
BBI608 on Day 1 of Cycle 1 until Day 24 pre-dose examination. DLT will be assessed 
in Phase 1 part only. 
 
4.4.3 
Follow-up observation period 
The follow-up observation period is defined as the period from the day of the last dose 
of BBI608 until the examination/observation 28 days later or until the 
examination/observation before subsequent treatment if subsequent treatment is given 
within 28 days after the last dose of BBI608. 
 
4.4.4 
Patient outcome investigation 
Patient outcome investigation will be conducted 6 months and 1 year after last 
subject’s treatment start date. Additional patient outcome investigation will be 
conducted after 1 year since last subject’s treatment start date by sponsor requirement. 
 
4.5 
Schedule of assessments 
The clinical study schedule is shown in Table 1 (Phase 1 part) and Table 2 (Phase 2 
part). Schedule of imaging is shown in Table 3 (Phase 1 and 2 parts). Pharmacokinetic 
study schedule is shown in Table 4. The day of the first dose of BBI608 is defined as 
Day 1 by each cycle. 
 
 






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m) 
Cycle 1 treatment is given for 23 days; data up to Day 24 examination will be regarded Cycle 1 data.  
n) 
Performed before BBI608 administration.  
o) 
If Day 1 of Cycle 2 is the same day as Day 24 of Cycle 1, the procedures scheduled for Day 1 of Cycle 2 will be omitted with the exception of “BBI608 administration, compliance” 
and “Pem and CDDP administration, compliance.” 
p) 
If these were performed on the day of before Pem and CDDP administration, the data may be alternatively used. If Pem and CDDP were discontinued, these will be performed 
every 21 days (± 7 days) starting the day following the end of the last cycle.  
q) 
Not required if Pem and CDDP were discontinued.   
r) 
If subsequent treatment is started during the follow-up observation period, these will be performed before subsequent treatment. Available data obtained within 14 days before the 
start of subsequent treatment may be alternatively used.  
s) 
If judged necessary by the sponsor, patient outcome investigation may be continued beyond 6 months after last subject’s treatment start date.  
 
 




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f) 
Available data obtained within 28 days before enrollment may be alternatively used.  
g) 
Performed within 3 days before the start of study treatment.  
h) 
If screening examination was performed within 7 days before the start of BBI608 administration, the results 
from screening examination may be used as baseline data. If screening examination was performed ≥ 7 days 
before the start of BBI608 administration, baseline data should be newly obtained before the start of BBI608 
administration.   
i) 
Performed after BBI608 administration.  
j) 
If these were performed on the day of before Pem and CDDP administration, the data may be alternatively used. 
If Pem and CDDP were discontinued, these will be performed every 21 days (± 7 days) starting the day 
following the end of the last cycle.   
k) 
Not required if Pem and CDDP were discontinued.  
l) 
If subsequent treatment is started during the follow-up observation period, these will be performed before 
subsequent treatment. Available data obtained within 14 days before the start of subsequent treatment may be 
alternatively used.  
m) 
If judged necessary by the sponsor, patient outcome investigation may be continued beyond 6 months after last 
subject’s treatment start date.   
 
 
 
 
 
 


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Table 3 Schedule of Imaging and Respiratory function tests in Phase 1 and 2 Parts 
Months 
- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
… 
Weeks 
- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 33 
… 
Imaging 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
Respiratory 
function 
tests 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
 
 
Imaging and respiratory function tests requirements are as follows:  
- For screening imaging, available imaging obtained within 14 days before enrollment may be alternatively used if the imaging conditions were in line with the RECIST 1.1 for NSCLC 
patients or the mRECIST for MPM patients. 
- Respiratory function tests will be performed within 7 days before the start of BBI608 administration. 
- The allowable range for imaging and respiratory function tests are ±1 week. Imaging and respiratory function tests will be obtained every 6 weeks from the first dose of BBI608 (Day 
1 of Cycle 1) until Week 30, and then every 9 weeks from Week 31 on. The schedule of imaging and respiratory function tests are based only on Day 1 of Cycle 1, irrespective of Day 
1 of Cycle 2 or any later cycle.  
- If protocol treatment is discontinued because of imaging-documented worsening, no further imaging and respiratory function tests are required.  
- If protocol treatment is discontinued for other reasons than imaging-documented worsening, imaging and respiratory function tests will be continued according to the imaging 
schedule even after discontinuation of protocol treatment. If subsequent treatment is started, imaging and respiratory function tests will be performed before subsequent treatment as 
far as possible, and no further imaging and respiratory function tests are required after initiation of subsequent treatment.  
 
 
 
6 weeks 
6 weeks 
6 weeks 
9 weeks 
6 weeks 
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4.6 
Determination of sample size 
Phase 1 part: 3 to 6 subjects evaluable for DLT. 
Phase 2 part: 20 subjects given protocol treatment at least once, including 15 subjects 
with epithelioid histology. 
 
5. Analysis population 
5.1 
Safety analysis population 
The safety analysis population will consist of all subjects received the investigational 
drug. 
 
5.2 
DLT evaluable population 
The DLT evaluable population will consist of subjects who received the investigational 
drug in Phase 1 part and met either of the following: 
- 
Subjects with a ≥ 80% BBI608 treatment compliance rate during the DLT 
evaluation period, as calculated by the following formula: 
[Amount of BBI608 actually taken/ (480 mg × 45)] × 100 (%) 
- 
Subjects with onset of DLT during the DLT evaluation period. 
 
5.3 
Pharmacokinetics analysis population 
The pharmacokinetics analysis population will consist of subjects who received BBI608 
with the post-dose plasma BBI608 concentration data available for at least one time 
point. 
 
5.4 
Efficacy analysis population (modified ITT population: mITT 
population) 
Subjects who received the investigational drug. 
 
6. Safety and efficacy endpoints 
6.1 
Phase 1 part 
6.1.1 
Safety endpoints 
- 
Adverse event, adverse drug reaction and DLT 
- 
Vital signs and body weight 
- 
Laboratory test values 
- 
12-lead ECG 
- 
Chest X-ray 
- 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 
 


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6.1.2 
Efficacy endpoints 
- 
Tumor response (Response rate [RR], Disease control rate [DCR]) 
- 
Duration of response 
- 
Duration of disease control 
- 
PFS 
- 
OS 
- 
Respiratory function tests (Vital capacity [VC], Forced vital capacity [FVC], 
Forced expiratory volume in 1st second [FEV1]) 
 
6.1.3 
Pharmacokinetic endpoints 
BBI608 pharmacokinetic parameters of the following: 
- 
Maximum observed plasma concentration (Cmax) 
- 
Minimum observed plasma concentration (Cmin) 
- 
Area under the plasma concentration-time curve from time zero to 12 hours 
(AUC0-12) 
- 
Area under the plasma concentration-time curve from time zero to 24 hours 
(AUC0-24)  
- 
Area under the plasma concentration-time curve from time zero to infinity 
(AUC0-∞)  
- 
Percent of AUC0-∞ due to extrapolation from last non-zero data time to infinity 
(AUC% extrapolated) 
- 
Time to maximum observed plasma concentration (tmax)  
- 
Terminal elimination rate constant (λz)  
- 
Terminal elimination half-life (t1/2)  
- 
Mean residence time (MRT) 
 
6.2 
Phase 2 part 
6.2.1 
Efficacy endpoints 
6.2.1.1 
Primary endpoint 
- 
PFS 
 
6.2.1.2 
Secondary endpoints 
- 
OS 
- 
Tumor response (Response rate [RR], Disease control rate [DCR]) 
- 
Duration of response 
- 
Duration of disease control 
- 
Respiratory function tests (Vital capacity [VC], Forced vital capacity [FVC], 


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Forced expiratory volume in the first second [FEV1]) 
 
6.2.2 
Safety endpoints 
- 
Adverse event and adverse drug reaction 
- 
Vital signs and body weight 
- 
Laboratory test values 
- 
12-lead ECG 
- 
Chest X-ray 
- 
ECOG PS 
 
6.2.3 
Other endpoints 
- 
Biomarkers (pSTAT3 Nuclear Tumor, Beta-catenin Nuclear Tumor, Merlin 
Tumor) 
 
 
7. General data handling 
7.1 
Definition and data handling 
Detailed data handling will be defined before database lock. 
Order of data handling process is as follows; 1) Determine the data excluded from 
analysis. 2) Determine analysis visit and baseline. 
 
7.1.1 
Data excluded from the analyses 
7.1.1.1 
Upper/Lower limit of quantification (ULOQ/LLOQ) 
Where applicable, the upper limit of quantification (ULOQ) will be substituted for 
chemistry, hematology, urinalysis, and urine microscopic values that are greater than the 
ULOQ. Similarly, if the value is below the lower limit of quantification (LLOQ), then 
the LLOQ will be substituted. 
 
7.1.1.2 
Vomiting 
When the subject experiences vomiting within 8 hours after the dose of BBI608 in the 
morning at Day 1, Day 3, Day 23 and Day 24 whose all plasma concentrations data will 
be excluded from analysis in principle. The handling of plasma concentrations data with 
vomited subject will be decided in blinded data review meeting. 
 
7.1.1.3 
Violation from blood sampling time 
In case that the error in blood sampling time for BBI608, the plasma concentration data 
will be not included the calculation of summary statistics by nominal time point, but 




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7.1.2.2 
Study Day 
The day of the first dose of BBI608 is defined as Day 1 of study day. 
 
 
7.1.2.3 
Visit windows and termination window 
Visit windows (analysis window) will not be used for this study. Instead, all analyses 
will use the scheduled visits recorded on the CRF including termination visit. This rule 
will be applied all efficacy and safety endpoints to be analyzed. 
 
7.1.3 
Handling of missing data 
7.1.3.1 
Safety endpoints 
Missing data will not be imputed. 
For laboratory samples that are not evaluable, the corresponding laboratory records will 
not be used in analyses and only be listed as part of the listings. Non-evaluable records 
will be determined prior to database lock and provided separately from this SAP. 
 
7.1.3.2 
Efficacy endpoints 
Any individual missing item in any scale will not be imputed. 
 
7.1.3.3 
Others 
7.1.3.3.1 
Partial date 
If partial dates of “Date of Diagnosis of Primary Cancer” in cancer history are reported, 
impute first date of the month/first month of the year. Partial dates for others will not be 
imputed. 
 
7.1.4 
Prior and Concomitant medications 
7.1.4.1 
Prior medications 
Prior medications are defined as medications that were taken before start of study drug. 
 
7.1.4.2 
Concomitant medications 
Concomitant medications are defined as medications that of administration period were 
overlapped with study drug administration period. 
 
 
7.2 
Statistical methodology 
7.2.1 
Software 
All PK parameter estimation will be carried out using Phoenix® WinNonlin® (version 


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6.3 or a more recent version). 
Computations for all of the results will be performed using SAS version 9.4 or higher 
computer software package, unless otherwise specified. 
 
7.2.2 
Summary statistics 
Categorical parameters will be summarized by presenting the number and percentage of 
subjects in each category.  
Continuous parameters will be summarized using n, mean, standard deviation (SD), 
median, minimum (min), and maximum (max) values. Coefficient of variation (CV%), 
geometric mean and geometric CV% will be added for the summary of plasma 
concentration. Coefficient of variation and geometric CV% will be displayed at the one 
decimal place. 
Geometrics mean and geometric CV% are calculated by following SAS code. 
 
ods listing close ; 
proc ttest data=[dataset] dist=lognormal ; 
    var [variable] ; 
    ods output statistics=[dataset] ; 
run ; 
ods listing ; 
 
7.2.3 
Significant level and p value, confidential interval 
Since no statistical test will be performed, level of significance will not be set. 
 
7.2.4 
Multiple comparison/Multiplicity 
Not apply the statistical method for multiplicity in this study. 
 
7.2.5 
Definition of terms 
Definition of each item is presented below. For a derived variable, the computed value 
is used for the analysis without rounding, in general. Rounding is just made when the 
result is presented in tables or listings. 
- 
Study day (relative day from the date of the first dose of BBI608): 
Assessment date – the date of the first dose of BBI608 + 1 (On or after the date 
of the first dose of BBI608) 
Assessment date – the date of the first dose of BBI608 (Before the date of the 
first dose of BBI608) 
- 
Month: 365.25/12=30.4375 day 


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- 
Week: 7 day 
- 
Disease duration (month): (Date of Informed consent − Date of diagnosis of 
primary cancer + 1)/30.4375 
- 
Treatment compliance of BBI608 (%): See 8.5.1 
- 
Treatment intensity of BBI608 (%), Pem/CDDP: See 8.5.1 
- 
Mean daily dose (mg/day): See 8.5.4 
- 
Modal daily dose (mg/day): See 8.5.5 
 
 
8. Analysis of subjects 
8.1 
Disposition of subjects 
The following will be summarized for entire study and separately for Phase 1 part and 
Phase 2 part: 
- 
Number of enrolled subjects 
- 
Number of start BBI608 administration subjects 
- 
Number of discontinued subjects during DLT evaluation period (Phase 1 part 
only) 
- 
Number of subjects completing DLT evaluation period (Phase 1 part only) 
- 
Number of discontinued subjects after administration 
- 
Number of subject completing survival follow-up observation period 
- 
Number of discontinued subjects before survival follow-up observation period 
 
Reason for discontinuation will be summarized and listed for entire study and separately 
for Phase 1 part and Phase 2 part. A listing of cause of death and survival follow-up will 
be provided. 
 
8.2 
Important Protocol Deviation 
Important protocol deviations will be detected at BDRM and listed. 
 
8.3 
Analysis population 
The number of subjects within each analysis population will be summarized for entire 
study and separately for Phase 1 part and Phase 2 part. 
- 
Safety analysis population 
- 
DLT evaluable population (Phase 1 part only) 
- 
Pharmacokinetic (PK) analysis population (Phase 1 part only) 
- 
modified ITT (mITT) population 
 


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8.4 
Demographic and other baseline characteristics 
In each analysis population, and separately for Phase 1 part, Phase 2 part and Phase 2 
part (including subjects with MPM in Phase 1 part), summary statistics will be 
calculated for following demographics and baseline charactertistics: 
- 
Sex: Male/Female 
- 
Age (year): summary statistics 
- 
Ethnicity: Not Hispanic or Latino 
- 
Race: Asian 
- 
Weight (kg): summary statistics 
- 
ECOG PS: 0, 1, 2≤ 
- 
Disease Classification (NSCLC): Stage I, Stage II,  Stage IIIA, Stage IIIB, 
Stage IV 
- 
Disease Classification (MPM): Stage I, Stage II, STAGE III, Stage IV 
- 
Primary cancer: Malignant Pleural Mesothelioma (MPM), Non-Small Cell 
Lung Cancer (NSCLC) 
- 
Tissue Classification (MPM): Epithelioid, Sarcomatoid, Biphasic, Other 
- 
Tissue Classification (NSCLC): Adenocarcinoma, Squamous Cell Carcinoma, 
Large Cell Carcinoma, Other 
- 
Metastasis: Yes, No 
- 
Disease duration (month): summary statistics 
 
Output Phase 1 part only in PK and DLT evaluate population. 
 
8.5 
Measurements of treatment compliance 
In safety analysis, DLT evaluable, PK analysis population and mITT population, and 
separately for Phase 1 part, Phase 2 part and Phase 2 part (including subjects with MPM 
in Phase 1 part), summary tables will be provided. 
The calculation will be conducted in DLT evaluation period in DLT evaluable and PK 
analysis populations for Phase 1 part only. 
 
8.5.1 
Treatment compliance and intensity 
Treatment compliance of BBI608 and treatment intensity of BBI608 and Pem/CDDP 
will be summarized and listed. 
Treatment compliance/intensity will be calculated as follows: 
 
BBI608 
- 
Overall treatment compliance (%) of BBI608: 100×(total number of actual 


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ingested capsules)/(total number of prescribed capsules) 
- 
Overall treatment intensity (%) of BBI608: 100×(total number of actual 
ingested capsules)/(12×study duration-6), where phase 1 part subject 
Overall treatment intensity (%) of BBI608: 100×(total number of actual 
ingested capsules)/(12×study duration), where phase 2 part subject 
- 
Treatment intensity (%) of BBI608 at DLT evaluation period: 100×(total 
number of actual ingested capsules at DLT evaluation period)/270 
- 
Study duration: Date of last administration of BBI608 – Date of first 
administration of BBI608 + 1 
 
Pem 
- 
Overall treatment intensity (%) of Pem: 100×[total amount of actual injected 
pemetrexed (mg/m2)]/[total time of injected pemetrexed×500 (mg/m2)] 
 
CDDP 
- 
Overall treatment intensity (%) of CDDP: 100×[total amount of actual injected 
cisplatin (mg/m2)]/[total time of injected cisplatin×75 (mg/m2)] 
 
 
8.5.2 
Duration of exposure 
Duration of exposure by month of BBI608 will be summarized and listed. 
Duration of exposure by day of BBI608 will be summarized for DLT evaluable 
population and listed. 
Count the number of subject and percentage who received both of Pem and CDDP more 
than or equal 6 cycles. 
 
8.5.3 
Cumulative dose 
Cumulative dose of BBI608, Pem and CDDP will be summarized and listed. 
 
8.5.4 
Mean daily dose 
Mean daily dose of BBI608 will be listed.  
Mean daily dose will be calculated as follows: 
- 
Overall mean daily dose (mg/day) = Cumulative dose of BBI608/Study 
duration 
 
8.5.5 
Modal daily dose 
Modal daily dose of BBI608 in phase 2 part will be listed. 


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If subject has two or more most frequent daily doses, handle the highest dose as modal 
daily dose. 
Example 
- 
Treatment duration (daily dose): 50 days (160 mg/day), 40 days (480 mg/day), 
50 days (960 mg/day) 
- 
Modal daily dose: 960 mg/day 
 
8.6 
Prior and Concomitant medications 
Prior and concomitant medications will be coded to ATC (Anatomical Therapeutic 
Chemical) classification and Drug Name using WHO Drug Dictionary (WHODrug) 
version September, 2014. 
Prior and concomitant medications will be provided by level 3 ATC classification and 
preferred name using frequencies and percentages in the Safety and mITT analysis 
population separately for Phase 1 part, Phase 2 part and Phase 2 part (including subjects 
with MPM in Phase 1 part). 
 
 
9. Analysis of efficacy assessment 
All analysis for efficacy will be performed in mITT analysis population. 
 
9.1 
Definition of efficacy endpoint 
9.1.1 
Progression Free Survival (PFS) 
PFS time is defined as the time from the date of enrollment until the date of first 
radiographic documentation of progression as defined by RECIST (Version 1.1), or 
death due to any cause, whichever is first. 
The following table summarizes the censoring rules for the PFS analysis: 
 
Situation 
Date of Event or Censor 
Event / Censor 
No baseline radiological tumor 
assessment available 
Day 1 
Censored 
No post baseline radiological tumor 
assessment available and no death 
reported until Day 91 
Day 1 
Censored 
No post baseline radiological tumor 
assessment available 
but death reported until Day 91 
Date of Death 
Event 
No tumor progression (per 
RECIST 1.1) and no death reported 
within 2 radiological tumor 
assessments following last adequate 
radiological tumor assessment 
Date of last adequate radiological 
tumor assessment 
Censored 


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No tumor progression (per 
RECIST 1.1) but death reported 
within 2 radiological tumor 
assessments following last adequate 
radiological tumor assessment 
Date of death 
Event 
New anticancer treatment started 
and no tumor progression 
Date of previous adequate 
radiological assessment 
immediately prior to start of new 
therapy 
Censored 
No tumor progression (per 
RECIST 1.1) and subject lost to 
follow-up or withdrawal of consent 
Date of last adequate radiological 
Assessment 
Censored 
 
 
 




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9.1.2 
Overall Survival (OS) 
OS is defined as the time from BBI608 administration to death from any cause. Subjects 
alive at final observation or lost to follow-up will be censored at their last contact (i.e., 
visit or telephone) date. 
 
9.1.3 
Response Rate (RR) 
RR is defined as the proportion of subjects with either Complete Response (CR) or 
Partial Response (PR). 
 
9.1.4 
Disease Control Rate (DCR) 
DCR is defined as the proportion of patients with CR, PR or Stable Disease (SD). 
 
9.1.5 
Duration of response 
Duration of response is calculated as follows: 
Duration of response (month) = (the first date of PD evaluation or death – the first date 
of CR or PR evaluation)/30.4375 
 
9.1.6 
Duration of disease control 
Duration of disease control is calculated as follows: 
Duration of disease control (month) = (the first date of PD evaluation or death – the first 
date of BBI608 administration)/30.4375 
 
9.2 
Phase 1 part 
Data from MPM patients and NSCLC patients will be combined for efficacy analysis. 
 
9.2.1 
Tumor response 
The best overall response according to RECIST 1.1 or mRECIST, RR and DCR will be 
summarized. 
Duration of response and duration of disease control will be summarized. 
 
9.2.2 
Progression Free Survival (PFS) 
Survival curve of PFS will be displayed by Kaplan-Meier method. Median survival time 
(MST) of PFS will be calculated. 
 
9.2.3 
Overall Survival (OS) 
Survival curve of OS will be displayed by Kaplan-Meier method. MST of OS will be 
calculated. 


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9.2.4 
Respiratory Function Tests 
The measurement of respiratory function tests (vital capacity [VC], forced vital capacity 
[FVC] and forced expiratory volume in 1st second [FEV1]) and their change from 
baseline will be summarized by visit. 
 
9.3 
Phase 2 part 
The efficacy data from MPM subjects in Phase 1 part will be included in the Phase 2 
part efficacy analysis. 
 
9.3.1 
Primary endpoints 
Survival curve of PFS will be displayed by Kaplan-Meier method. MST of PFS and the 
95%CI will be calculated. In addition, 6-month PFS rate and the 95%CI will be 
calculated. 
 
9.3.2 
Secondary endpoints 
- 
Survival curve of OS will be displayed by Kaplan-Meier method. MST of OS 
and the 95%CI will be calculated. In addition, 1-year OS rate and the 95%CI 
will be calculated. 
- 
The best overall response according to RECIST 1.1 or mRECIST, RR and 
DCR will be summarized. 
- 
Duration of response and duration of disease control will be summarized. 
- 
Scatter plots biomarker vs. PFS and OS by all MPM subject and epithelioid 
subject will be provided. 
Biomarker: H-score and Total percent positive of pSTAT3 Nuclear Tumor, 
Bete-catenin Nuclear Tumor and Merlin Tumor. 
H score of pSTAT3 Nuclear Tumor is calculated by [Percent Tumor Staining 1] 
+ [Percent Tumor Staining 2] * 2 + [Percent Tumor Staining 3] * 3 
The measurement of respiratory function tests (vital capacity [VC], forced vital capacity 
[FVC] and forced expiratory volume in 1st second [FEV1]) and their change from 
baseline will be summarized by visit. 
 
9.3.3 
Subgroup analysis 
Subgroup analysis will be performed for MPM subjects according to tissue 
classification (epithelioid, sarcomatoid, biphasic) for following: 
- 
Survival curve of PFS will be displayed by Kaplan-Meier method. MST of 
PFS, 6-month PFS rate and their 95%CI will be calculated. 


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- 
Survival curve of OS will be displayed by Kaplan-Meier method. MST of OS, 
1-year OS rate and their 95%CI will be calculated. 
- 
The best overall response according to RECIST 1.1 or mRECIST, RR and 
DCR will be summarized. 
- 
Duration of response and duration of disease control will be summarized. 
- 
The measurement of respiratory function tests (vital capacity [VC], forced vital 
capacity [FVC] and forced expiratory volume in 1st second [FEV1]) and their 
change from baseline will be summarized by visit. 
 
 
10. Analysis of Safety assessment 
Safety will be analyzed using the safety analysis population, and the data will be 
summarized for the entire study and separately for Phase 1 part, Phase 2 part and Phase 
2 part (including MPM subjects in Phase 1 part). 
 
10.1 Adverse Events 
Adverse event (AE) is defined as all adverse events reported in CRF. Adverse drug 
reaction (ADR) is defined as an event whose relationship to study medication is NOT 
“not related” and “unlikely”. 
 
10.1.1 
Overall summary of AEs 
The number and percentage of subjects with following will be calculated. 
- 
AE/ADR 
- 
AE/ADR leading to death 
- 
serious AE/ADR 
- 
AE/ADR leading to drug withdraw (BBI608/Pem/CDDP) 
- 
AE/ADR leading to drug interrupt (BBI608/Pem/CDDP) 
- 
AE/ADR leading to dose reduced (BBI608/Pem/CDDP) 
The listing of survival follow up will be reported. 
 
10.1.2 
Summary of AE by MedDRA 
The number and percentage of subjects with AE/ADR using MedDRA SOC and PT will 
be calculated. The similar table by severity (grade) will be reported. 
 
10.1.3 
Summary of AE by onset 
The number and percentage of subjects with AE onset each following exposure intervals 
using MedDRA SOC and PT will be calculated. 


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a. 1-3 days, 4-7 days, 8-14 days, 15-24 days 
b. 1-28 days, 29-56 days, 57-84 days, 85-112 days, 113-140 days, 141-168 days, 
169-196 days, 197days-, Overall 
Denominators for exposure intervals will be based on the number of subjects who were 
exposed as of the first day of the interval. 
If subject has two or more same AE in same exposure interval, count up as one subject. 
 
10.1.4 
Summary of AE by first onset 
The number and percentage of subjects with first onset event of each AE will be 
calculated. The exposure interval will be used same with “10.1.3 Summary of AE by 
onset”. 
 
10.2 DLT evaluation 
Tables and lists regarding DLT evaluation will be provided using DLT evaluable 
population for subjects in Phase 1 part. 
The number and percentage of subjects with DLT for DLT evaluate population will be 
calculated. Adverse events which are met definition of DLT but are not handled as DLT 
will be listed. 
 
10.3 Clinical laboratory evaluation 
10.3.1 
Summary of hematology and biochemistry 
Summary statistics for observed value and change from baseline will be calculated by 
analysis visit. 
The line chart by individual will be displayed. 
 
10.3.2 
Summary of urinalysis 
Urinalysis tests with categorical results will be summarized by analysis visit and shift 
table will be displayed at baseline and post-baseline worst case. 
 
10.3.3 
Summary of CTCAE grade 
The results of laboratory parameters will be graded according to NCI CTCAE v4.03 
(See chapter 13). The CTCAE grading will be performed based on only observed value 
without considering any clinical symptoms or findings. The highest grade will be 
defined as the maximum grade throughout the study and decided for each laboratory 
parameter. 
a. The number of percentage of subjects with the highest grade by laboratory 
parameters will be calculated. Denominators of percentage will be based on the 


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number of subjects who have at least one graded observed value besides baseline 
assessment. 
b. The shift from baseline grade to highest grade at post-baseline will be produced to 
show the number of subjects with corresponding changes. 
c. Listing will be provided by subjects and laboratory parameters. 
 
10.3.4 
Potential Clinical Significant 
The number and percentage of subjects will be calculated with potential clinical 
significant (PCS). PCS will be provided in the results of laboratory test listing. The 
criteria of PCS are shown in Chapter 12. 
 
10.4 Vital signs and Body weight evaluation 
Summary statistics for observed value and change from baseline will be calculated by 
analysis visit. 
 
10.5 12-lead ECG evaluation 
12-lead ECG with categorical results will be summarized by analysis visit. 
The shift from baseline to worst result at post-baseline will be produced to show the 
number of subjects. (Order of results: Normal > Abnormal [NCS] > Abnormal [CS]) 
 
10.6 ECOG PS evaluation 
ECOG PS with categorical results will be summarized by analysis visit and shift table 
will be displayed at baseline and post-baseline worst case. 
 
10.7 Chest X-ray evaluation 
Chest X-ray with categorical results will be listed. 
 
 
11. Analysis of Pharmacokinetics assessment 
All analysis for PK evaluation will be performed for pharmacokinetics analysis 
population. 
 
11.1 Handling of data 
Actual sampling time will be used for calculating PK parameters of plasma 
concentration. The pre-dose sampling time will be set to zero, and will also be reported 
as such (i.e. if the actual pre-dose time is -0.5 h, report the pre-dose time as 0 h for PK 
analysis). For PK parameters and summary statistics, all below limit of quantitation 


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(BLQ: less than 5.00 ng/mL for BBI608, less than 10.0 ng/mL for pemetrexed, less than 
25.0 ng/mL for cisplatin) values will be set to zero. 
 
11.1.1 
Reporting conventions 
For the listing, λz, t1/2 and MRT will be rounded to three decial places, tmax and AUC% 
extrapolated will be rounded to two decimal places, and Cmin will be rounded to one 
decimal place, and AUCs, Cmax, and number of points for λz will be rounded to integer. 
 
11.2 Method of PK parameter estimation 
The following PK parameters will be estimated from the BBI608 concentration data at Day 1 and 
Day 23 in Cycle 1 and the actual post-dose time. 
- 
Cmax: Maximum observed plasma concentration will be obtained directly from the 
concentration-time data. 
- 
AUC0-t: Area under the concentration-time curve up to the nominal sampling point (=12 
and 24 h) will be calculated by linear trapezoidal method. 
- 
AUC0-∞: Area under the concentration-time curve up to the last non-zero observed 
concentration time point (AUC0-last) will be calculated by linear trapezoidal method, plus 
“foot slope” area extrapolated by λz, i.e. the observed AUC0-∞ will be reported. 
- 
AUC% extrapolated will be calculated as (AUC0-∞ /AUC0-last)/AUC0-∞ ×100 
 
 
- 
λz: The elimination rate constant will be determined by linear regression of logarithmic 
transformed concentration-time data. For the linear regression analysis, at least three 
observations from the last measurable observed concentration (Clast(obs)) up to 
Cmax(exclusive), will be selected according to the “Adjusted R-square”. 
In the PK parameter listing, percent of AUC0-∞ extrapolated and number of data points 
for λz will be reported as the supportive information for λz and AUC0-∞. 
- 
t1/2: Terminal half-life is will be calculaed as ln(2)/λz. 
- 
tmax: Time to Cmax will be directly observed from the concentration-time data. If more than 
one time points which give Cmax exist, the one which comes first will be adopted. 
- 
MRT: Mean residence time will be calculated as the ratio of area under the first moment of 
the concentration-time curve (AUMC) to observed AUC0-∞. 
- 
Cmin: Minimum observed plasma concentration during a dosing interval at the steady state. 
 
Plasma concentration of BBI608, Pem, and CDDP by each time point will be summarized. 
The following chart will be provided: 
- 
Line chart of BBI608 concentration by individual at Day 1 and Day 23 in 
Cycle 1 (linear and logarithmic scale) 


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- 
Scatter plot of BBI608/Pem/CDDP concentration by individual at Day 3 in 
Cycle 1 
- 
Scatter plot of BBI608 Cmax, AUC0-12, and AUC0-24 at Day 1 and Day 23 
 
 
12. Clinical significant laboratory abnormalities 
Parameter (unit) 
Change 
Criteria 
Leukocyte count (x10^3/μL) 
increase 
100 < val 
Leukocyte count (x10^3/μL) 
decrease 
val < 2 
Erythrocyte count (x10^6/μL) 
decrease 
val ≤ 3 
Hemoglobin (g/dL) 
increase 
ULN+4 < val 
Hemoglobin (g/dL) 
decrease 
val < 8 
Hematocrit (%) 
decrease 
Male: val ≤ 37, Female: val ≤ 32 
Platelets (x10^4/μL) 
increase 
70 ≤ val 
Platelets (x10^4/μL) 
decrease 
val < 5 
Neutrophil count (x10^9/L) 
decrease 
val < 1 
Lymphocyte count (x10^9/L) 
increase 
20 < val 
Lymphocyte count (x10^9/L) 
decrease 
val < 0.5 
Protein (g/dL) 
decrease 
val < 4.5 
Albumin (g/dL) 
decrease 
val < 2 
Bilirubin (mg/dL) 
increase 
3×ULN < val 
Aspartate Aminotransferase (U/L) 
increase 
5×ULN < val 
Alanine Aminotransferase (U/L) 
increase 
5×ULN < val 
Alkaline Phosphatase (U/L) 
increase 
5×ULN < val 
Lactate Dehydrogenase (U/L) 
increase 
3×ULN ≤ val and 1.2×BL ≤ val 
Blood Urea Nitrogen (mg/dL) 
increase 
30 < val 
Creatinine (mg/dL) 
increase 
3×ULN < val 
Creatinine (mg/dL) 
increase 
BL+4 < val 
Sodium (mEq/L) 
increase 
155 < val 
Sodium (mEq/L) 
decrease 
val < 130 
Potassium (mEq/L) 
increase 
6 < val 
Potassium (mEq/L) 
decrease 
val < 3 
Chloride (mEq/L) 
increase 
115 < val 
Chloride (mEq/L) 
decrease 
val < 90 
Calcium (corrected) (mg/dL) 
increase 
12.5 < val 
Calcium (corrected) (mg/dL) 
decrease 
val < 7 
Magnesium (mg/dL) 
increase 
3 < val 
Magnesium (mg/dL) 
decrease 
val < 0.9 


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Glucose *3 
increase 
BL+2 ≤ val 
Blood *3 
increase 
BL+2 ≤ val 
Protein *3 
increase 
BL+2 ≤ val 
*3: Subjects whose baseline result is normal will be summarized. 
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