A Study of BBI608 in Combination With Pemetrexed and Cisp... | NCT02347917

NCT02347917

Status Module

Sponsor/Collaborators Module

Oversight Module

No data available

No data is available for this block.

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Label	Type	Description	Intervention Names
BBI608 puls pemetrexed and cisplatin	Experimental		Drug: BBI608 Drug: Pemetrexed Drug: Cisplatin

Name	Type	Description	Arm Group Labels	Other Names
BBI608	Drug	480 mg orally twice daily (960 mg total daily dose)	BBI608 puls pemetrexed and cisplatin

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Phase 1 Part: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Drug Reactions (ADRs)	An AE 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. A SAE was an AE that met one or more of the following criteria: Results in death Is life-threatening 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. An ADR was defined as adverse events assessed to be related to the investigational drug	Between initial dosing of the investigational drug and final evaluation in the follow-up observation period, about 17 months
Phase 1 Part: Number of Participants With Dose-limiting Toxicities (DLTs)	DLT was defined as an adverse event meeting any of the following that occurred during the DLT evaluation period in any participants given BBI608 with the causal relationship to BBI608 assessed as "Definite," "Probable," or "Possible." The severity of adverse events was graded according to the CTCAE v4.0-JCOG. 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: Inappetence, nausea, vomiting and electrolyte abnormality which, within 3 days of onset, improved to grade ≤ 2 or resolved after appropriate treatment 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	From Day 1 of Cycle 1 to Day 24 pre-dose examination (23 days)
Phase 1 Part: Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of BBI608 When Administered With Pem and CDDP

Secondary Outcomes

Measure	Description	Time Frame
Best Overall Response	The best overall response is the best response recorded from the start of the study treatment until the end of treatment. The RECIST 1.1 was 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. The mRECIST was used for the evaluation of tumor response and overall response in patients with MPM. The result of imaging assessment by study site was used for phase 1 part, and the result of imaging assessment by the imaging assessment committee was used for phase 2 part.

Eligibility Module

Eligibility Criteria

Phase 1

Inclusion Criteria:

Histologically confirmed diagnosis of Malignant Pleural Mesothelioma (MPM) or Non-Small Cell Lung Cancer (NSCLC).
Measurable disease as defined by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) for MPM or the RECIST 1.1 for NSCLC.
≥ 20 years of age.
Provision of written informed consent.
For male or female patient of child producing potential: Must agree to use contraception or take measures to avoid pregnancy during the study and for 30 days after the last protocol treatment dose.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
Hemoglobin (Hb) ≥ 9.0 g/dL.
Neutrophils ≥ 1500/μL.
Platelets ≥ 100,000/μL.
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5-fold the upper limit of normal range (ULN) [≤ 5-fold ULN with any liver metastasis].
Total bilirubin ≤ 1.5-fold ULN.
Creatinine clearance (estimated value) ≥ 60 mL/min.
Life expectancy ≥ 3 months.
Females of childbearing potential have a negative urine pregnancy test.

Phase 2

Inclusion Criteria:

Histologically confirmed diagnosis of MPM.
Treatment naïve and not indicated for resection.
Measurable disease as defined by the modified RECIST.
≥ 20 years of age.
Provision of written informed consent.
For male or female patient of child producing potential: Must agree to use contraception or take measures to avoid pregnancy during the study and for 30 days after the last protocol treatment dose.
ECOG Performance Status of 0 or 1.
Hb ≥ 9.0 g/dL.
Neutrophils ≥ 1500/μL.
Platelets ≥ 100,000/μL.
AST and ALT ≤ 2.5-fold ULN [≤ 5-fold ULN for patients with any liver metastasis].
Total bilirubin ≤ 1.5-fold ULN.
Creatinine clearance (estimated value) > 60 mL/min.
Life expectancy ≥ 3 months.
Females of childbearing potential have a negative urine pregnancy test.

Both Phase 1 and 2

Exclusion Criteria:

Prior anti-cancer chemotherapy and radiotherapy.
Prior hormonal therapy, immunotherapy, thermotherapy, operation.
Any brain metastasis requiring treatment or symptomatic.
Active multiple primary cancers.
Crohn's disease, ulcerative colitis, small intestine resection.
Abnormal ECGs.
Prior myocardial infarction.
Current use of antiarrhythmic medication.
Uncontrolled concurrent diseases.
Known severe hypersensitivity to pemetrexed, cisplatin or other drugs containing platinum.
Women who are pregnant or breastfeeding.
Received other investigational drugs.
Unable or unwilling to swallow BBI608 capsules daily.
Prior treatment with BBI608.
Ineligible for participation in the study in the opinion of the Investigators.

Contacts/Locations Module

Name	Affiliation	Role
Sumitomo Pharma Co., Ltd. Japan	Sumitomo Pharma Co., Ltd.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
National Cancer Center Hospital East		Chiba			Japan
National Cancer Center Hospital

References Module

No data available

No data is available for this block.

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	MPM or NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jan 5, 2018	Oct 27, 2020

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Participants were NOT enrolled in Phase 1 and Phase 2 in duplicate.

Arm/Group Information

ID	Title	Description
BG000	MPM or NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.
BG001	MPM: BBI608 + Pem + CDDP (Phase 2 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG0004 BG00124 BG00228

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Any AEs

Title	Measurements
	OG0004

AEs leading to death

Title	Measurements
	OG0000

Serious AEs

Primary

Phase 1 Part: Number of Participants With Dose-limiting Toxicities (DLTs)

DLT was defined as an adverse event meeting any of the following that occurred during the DLT evaluation period in any participants given BBI608 with the causal relationship to BBI608 assessed as "Definite," "Probable," or "Possible." The severity of adverse events was graded according to the CTCAE v4.0-JCOG.

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:
1. Inappetence, nausea, vomiting and electrolyte abnormality which, within 3 days of onset, improved to grade ≤ 2 or resolved after appropriate treatment
2. 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 evaluable population (3 participants with NSCLC in Phase 1 part)

1 participant with MPM was excluded from DLT evaluable population because the BBI608 treatment compliance rate during DLT evaluation period did not meet the rate of 80% which of assessable for DLT and no adverse events assessed as DLT occurred.

Posted

Count of Participants

Participants

From Day 1 of Cycle 1 to Day 24 pre-dose examination (23 days)

ID	Title	Description
OG000	MPM or NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Primary

Phase 1 Part: Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of BBI608 When Administered With Pem and CDDP

Pharmacokinetic (PK) analysis population

1 participant with MPM of 4 participants in the pharmacokinetic analysis population completed BBI608 administration on Day 14 in Cycle 1 and therefore was not included in the analysis for Cmax and AUC on Day 23.

Posted

Mean

Full Range

ng/mL

Cycle 1 Day 1 (Cmax only) and Day 23

ID	Title	Description
OG000	MPM or NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Units	Counts
Participants	OG000

Primary

Phase 1 Part: Area Under the Concentration-time Curve

AUC0-12: Area under the concentration-time curve from time zero to 12 hours, AUC0-24: Area under the concentration-time curve from time zero to 24 hours, AUC0-inf: Area under the concentration-time curve from time zero to infinity

Pharmacokinetic (PK) analysis population

Posted

Mean

Full Range

h*ng/mL

Cycle 1 Day 1 and Day 23

ID	Title	Description
OG000	MPM or NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Units	Counts
Participants	OG000

Primary

Phase 2 Part: Progression-free Survival (PFS)

PFS was 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. The result of imaging assessment by the imaging assessment committee was used for phase 2 part.

modified ITT population. Efficacy was analyzed using the efficacy analysis population (i.e., modified ITT population; mITT), separately for Phase 1 part (n=4), Phase 2 part (n=24) and Phase 2 part including 1 participant with MPM in Phase 1 part (n=25).

Posted

Median

95% Confidence Interval

month

From BBI608 administration to documented PD or death, whichever is earlier, about 17 months

ID	Title	Description
OG000	MPM: BBI608 + Pem + CDDP (Phase 2 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.
OG001	MPM: BBI608 + Pem + CDDP (Phase 2 Part Including 1 Participant With MPM in Phase 1 Part)	Participants orally received BBI608(480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Secondary

Best Overall Response

The best overall response is the best response recorded from the start of the study treatment until the end of treatment. The RECIST 1.1 was 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. The mRECIST was used for the evaluation of tumor response and overall response in patients with MPM. The result of imaging assessment by study site was used for phase 1 part, and the result of imaging assessment by the imaging assessment committee was used for phase 2 part.

Posted

Count of Participants

Participants

Every 6 weeks from the first dose of BBI608 until Week 30, and every 9 weeks from Week 31.

ID	Title	Description
OG000	NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.
OG001	MPM: BBI608 + Pem +CDDP (Phase 1 Part)

Secondary

Response Rate (RR) and Disease Control Rate (DCR)

Response rate (RR): Proportion of subjects whose best overall response is CR or PR.

Disease control rate (DCR): Proportion of subjects whose best overall response is CR, PR or SD.

The result of imaging assessment by study site was used for phase 1 part, and the result of imaging assessment by the imaging assessment committee was used for phase 2 part.

Posted

Count of Participants

Participants

From BBI608 administration to death from any cause, about 17 months

ID	Title	Description
OG000	NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.
OG001	MPM: BBI608 + Pem +CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Secondary

Overall Survival(OS)

OS was defined as the time from BBI608 administration to death from any cause. Participants alive at final observation or lost to follow-up were censored at their last contact (i.e., visit or telephone) date.

Posted

Median

Full Range

month

From BBI608 administration to death from any cause, up to 31 months

ID	Title	Description
OG000	NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.
OG001	MPM: BBI608 + Pem +CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Secondary

Respiratory Function Tests (Vital Capacity [VC] and Forced Vital Capacity [FVC])

Posted

Median

Full Range

Every 6 weeks from the first dose of BBI608 until Week 30, and then every 9 weeks from Week 31 [Actually up to Week 111]

ID	Title	Description
OG000	NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.
OG001	MPM: BBI608 + Pem +CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Secondary

Respiratory Function Tests (Forced Expiratory Volume in the First Second [FEV1])

Posted

Median

Full Range

Every 6 weeks from the first dose of BBI608 until Week 30, and then every 9 weeks from Week 31 [Actually up to Week 111]

ID	Title	Description
OG000	NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.
OG001	MPM: BBI608 + Pem +CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	MPM or NSCLC: BBI608 + Pem + CDDP (Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.	2	4	0	4	4	4
EG001	MPM: BBI608 + Pem + CDDP (Phase 2 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.	19	24	7	24	24	24
EG002	MPM: BBI608 + Pem + CDDP (Phase 2 Part Including 1 Participant With MPM in Phase 1 Part)	Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles. Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.	21	25	7	25	25	25

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Colitis	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Enterocolitis	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Gastric ulcer	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Bronchopneumonia	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Sepsis	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Platelet count decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Neuroendocrine carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Delirium	Psychiatric disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Thrombosis	Vascular disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (17.1)	Systematic Assessment	EG0004 events4 affected4 at risk EG00115 events14 affected24 at risk EG00216 events15 affected25 at risk
Hearing impaired	Ear and labyrinth disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Tinnitus	Ear and labyrinth disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Vertigo positional	Ear and labyrinth disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Abdominal discomfort	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0010 events0 affected24 at risk EG0020 events0 affected25 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0013 events2 affected24 at risk EG0023 events2 affected25 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0013 events3 affected24 at risk EG0023 events3 affected25 at risk
Constipation	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG00122 events14 affected24 at risk EG00222 events14 affected25 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0008 events4 affected4 at risk EG00154 events24 affected24 at risk EG00255 events25 affected25 at risk
Faecal incontinence	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Gastritis	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0015 events5 affected24 at risk EG0025 events5 affected25 at risk
Haemorrhoids	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Nausea	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0005 events3 affected4 at risk EG00149 events21 affected24 at risk EG00251 events22 affected25 at risk
Stomatitis	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0015 events5 affected24 at risk EG0025 events5 affected25 at risk
Vomiting	Gastrointestinal disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG00117 events12 affected24 at risk EG00217 events12 affected25 at risk
Face oedema	General disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Fatigue	General disorders	MedDRA (17.1)	Systematic Assessment	EG0004 events2 affected4 at risk EG00110 events4 affected24 at risk EG00210 events4 affected25 at risk
Malaise	General disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG00111 events9 affected24 at risk EG00211 events9 affected25 at risk
Oedema peripheral	General disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG00111 events6 affected24 at risk EG00211 events6 affected25 at risk
Pyrexia	General disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0019 events7 affected24 at risk EG0029 events7 affected25 at risk
Conjunctivitis	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0010 events0 affected24 at risk EG0020 events0 affected25 at risk
Nasopharyngitis	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0013 events3 affected24 at risk EG0023 events3 affected25 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Alanine aminotransferase increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0013 events3 affected24 at risk EG0023 events3 affected25 at risk
Aspartate aminotransferase increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0013 events3 affected24 at risk EG0023 events3 affected25 at risk
Blood creatinine increased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0016 events6 affected24 at risk EG0026 events6 affected25 at risk
Creatinine renal clearance decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0013 events2 affected24 at risk EG0023 events2 affected25 at risk
Neutrophil count decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0007 events2 affected4 at risk EG00118 events12 affected24 at risk EG00219 events13 affected25 at risk
Platelet count decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0006 events2 affected4 at risk EG0015 events4 affected24 at risk EG0025 events4 affected25 at risk
Weight decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG00110 events6 affected24 at risk EG00210 events6 affected25 at risk
White blood cell count decreased	Investigations	MedDRA (17.1)	Systematic Assessment	EG0008 events2 affected4 at risk EG00111 events7 affected24 at risk EG00212 events8 affected25 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0009 events3 affected4 at risk EG00145 events21 affected24 at risk EG00246 events22 affected25 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0017 events4 affected24 at risk EG0027 events4 affected25 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0011 events1 affected24 at risk EG0021 events1 affected25 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0014 events3 affected24 at risk EG0024 events3 affected25 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0014 events4 affected24 at risk EG0024 events4 affected25 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG00113 events9 affected24 at risk EG00213 events9 affected25 at risk
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0010 events0 affected24 at risk EG0020 events0 affected25 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0019 events4 affected24 at risk EG0029 events4 affected25 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Dysgeusia	Nervous system disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0018 events6 affected24 at risk EG0029 events7 affected25 at risk
Headache	Nervous system disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG00110 events4 affected24 at risk EG00210 events4 affected25 at risk
Insomnia	Psychiatric disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0015 events4 affected24 at risk EG0025 events4 affected25 at risk
Chromaturia	Renal and urinary disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0014 events4 affected24 at risk EG0024 events4 affected25 at risk
Pollakiuria	Renal and urinary disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Renal impairment	Renal and urinary disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0016 events5 affected24 at risk EG0026 events5 affected25 at risk
Breast pain	Reproductive system and breast disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0010 events0 affected24 at risk EG0020 events0 affected25 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0013 events3 affected24 at risk EG0023 events3 affected25 at risk
Hiccups	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Systematic Assessment	EG0005 events3 affected4 at risk EG00122 events12 affected24 at risk EG00223 events13 affected25 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment	EG0001 events1 affected4 at risk EG0010 events0 affected24 at risk EG0020 events0 affected25 at risk
Urticaria	Skin and subcutaneous tissue disorders	MedDRA (17.1)	Systematic Assessment	EG0002 events1 affected4 at risk EG0010 events0 affected24 at risk EG0020 events0 affected25 at risk
Hypertension	Vascular disorders	MedDRA (17.1)	Systematic Assessment	EG0000 events0 affected4 at risk EG0012 events2 affected24 at risk EG0022 events2 affected25 at risk

ID	Term
D000086002	Mesothelioma, Malignant
D002289	Carcinoma, Non-Small-Cell Lung

Ancestor Terms

ID	Term
D008654	Mesothelioma
D000236	Adenoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D018301	Neoplasms, Mesothelial
D008175	Lung Neoplasms
D012142	Respiratory Tract Neoplasms
D013899	Thoracic Neoplasms
D009371	Neoplasms by Site
D010997	Pleural Neoplasms
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D002283	Carcinoma, Bronchogenic
D001984	Bronchial Neoplasms

ID	Term
C000621033	napabucasin
D000068437	Pemetrexed
D002945	Cisplatin

Ancestor Terms

ID	Term
D006147	Guanine
D007042	Hypoxanthines
D011688	Purinones
D011687	Purines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D005971	Glutamates
D024342	Amino Acids, Acidic
D000596	Amino Acids
D000602	Amino Acids, Peptides, and Proteins
D000600	Amino Acids, Dicarboxylic
D017606	Chlorine Compounds
D007287	Inorganic Chemicals
D017672	Nitrogen Compounds
D017671	Platinum Compounds

Title	Measurements
	OG0000

Participants orally received BBI608 (480 mg) twice daily plus intravenously received Pem (500 mg/m2) and CDDP (75 mg/m2) on Day 3 in only Cycles 1 and on Days 1 in Cycles 2 and subsequent cycles.

Premeditation with folic acid and vitamin B12 was given to reduce occurrence of serious adverse drug reactions, with reference to the package insert for Pem. Each cycle was defined as 21 days.