A Study of Napabucasin (BBI-608) in Combination With FOLFIRI in Adult Patients With Previously Treated Metastatic Colorectal Cancer (CanStem303C)

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ClinicalTrials.gov Identifier: NCT02753127

Recruitment Status : Completed

First Posted : April 27, 2016

Results First Posted : April 26, 2022

Last Update Posted : April 26, 2022

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Sumitomo Pharma Oncology, Inc.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Colorectal Cancer
Interventions	Drug: Napabucasin Drug: Fluorouracil Drug: Leucovorin Drug: Irinotecan Drug: Bevacizumab
Enrollment	1253

Participant Flow

Recruitment Details	1253 participants were randomized between October 2016 and March 2019.
Pre-assignment Details	Completers included patients who died, withdrew consent to survival follow up or were lost to follow up.


Arm/Group Title	Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description	Napabucasin 240 mg will be administ...	Addition of bevacizumab to the FOLF...
Arm/Group Description	Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion or at least 2 hours following the first daily dose of napabucasin if bevacizumab is not administered. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle	Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle.
Period Title: Overall Study
Started	624	629
Discontinued Due to Death	507	499
Completion of Survival Follow-Up Due to Study Completion	64	62
Completed	571	561
Not Completed	53	68
Reason Not Completed
Lost to Follow-up	13	11
Withdrawal by Subject	37	47
Other	3	8
Hospice	0	2

Baseline Characteristics

Arm/Group Title		Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab	Total
Arm/Group Description		Napabucasin 240 mg will be administ...	Addition of bevacizumab to the FOLF...	Total of all reporting groups
Arm/Group Description		Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion or at least 2 hours following the first daily dose of napabucasin if bevacizumab is not administered. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle.	Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle	Total of all reporting groups
Overall Number of Baseline Participants		624	629	1253
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	624 participants	629 participants	1253 participants
		60.1 (11.17)	59.6 (11.14)	59.8 (11.16)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	624 participants	629 participants	1253 participants
	Female	240 38.5%	254 40.4%	494 39.4%
	Male	384 61.5%	375 59.6%	759 60.6%
Race/Ethnicity, Customized ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	624 participants	629 participants	1253 participants
White		375	370	745
Black or African American		29	38	67
Asian		197	194	391
American Indian or Alaska Native		0	1	1
Native Hawaiian or Other Pacific Islander		1	0	1
Other		9	12	21
Missing		13	14	27
		[1] Measure Description: Race (White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Other)
Region of Enrollment ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	624 participants	629 participants	1253 participants
Singapore		8	9	17
Hong Kong		1	11	12
United States		203	209	412
Czechia		18	19	37
Japan		63	63	126
Spain		74	62	136
Canada		21	15	36
Netherlands		16	21	37
South Korea		44	39	83
Belgium		16	24	40
China		62	59	121
Italy		22	29	51
Israel		8	10	18
Australia		36	24	60
France		20	21	41
Germany		12	14	26
		[1] Measure Description: Region/Country(Australia, Balgium, Canada, China, Czech Republic, France, Germany, Hong Kong, Israel, Italy, Japan, Korea Republic of, Netherlands, Singapore, Spain, United States)
ECOG Performance Status ^[1] Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	624 participants	629 participants	1253 participants
ECOG: 0		333 53.4%	332 52.8%	665 53.1%
ECOG: 1		291 46.6%	297 47.2%	588 46.9%
		[1] Measure Description: The ECOG(Eastern Cooperative Oncology Group) Performance Status describes a patient's level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working, etc.). The higher the score, the more restricted the patient is clinically determined to be.

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS)
Description	Overall survival was defined as the time from randomization until deat...
Description	Overall survival was defined as the time from randomization until death from any cause. Patients who are alive at the time of the interim or the final analyses or who have become lost to follow-up will be censored on the date the patient was last known to be alive.
Time Frame	Randomization to Date of Death from any cause or database cutoff date (28 Apr 2020) (Approximately 43 months)

Outcome Measure Data

Analysis Population Description

The pSTAT3 subpopulations will be defined by the results of a Clinical Trial Assay (CTA) for a specimen with an age within a defined cut-section stability (CSS) window.

A patient with positive pSTAT3 status within a defined CSS window is the one with pSTAT3 positive designated by CTA with specimen age up to 6 months at interim analysis or up to the final CSS window at final analysis.


Arm/Group Title		Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description:		Napabucasin 240 mg will be administ...	Addition of bevacizumab to the FOLF...
Arm/Group Description:		Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion or at least 2 hours following the first daily dose of napabucasin if bevacizumab is not administered. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle.	Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle
Overall Number of Participants Analyzed		624	629
Median (95% Confidence Interval) Unit of Measure: months
Overall Survival (OS), General Population(GP)	Number Analyzed	624 participants	629 participants
Overall Survival (OS), General Population(GP)		14.29 (13.34 to 15.7)	13.83 (12.42 to 15.28)
Overall Survival (OS), ITT-pSTAT3(+)	Number Analyzed	275 participants	272 participants
Overall Survival (OS), ITT-pSTAT3(+)		13.17 (11.30 to 15.31)	12.12 (11.24 to 14.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	General population
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3629
	Comments	1-sided
	Method	Log Rank
	Comments	Based on stratified log-rank test stratified by actual stratification factors. P-value is nominal p-value without multiplicity adjustment.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.976
	Confidence Interval	(2-Sided) 95% 0.854 to 1.117
	Estimation Comments	Based on Cox Proportional hazards model stratified by actual stratification factors including Time to progression on 1st line therapy, RAS mutation, and Bev as part of study treatment. A HR <1 indicates a lower risk with Arm 1 compared with Arm 2.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	activated signal transducers and activators of transcription 3 (pSTAT3)-positive (pSTAT3(+)) Subpopulation patients
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3782
	Comments	1-sided
	Method	Log Rank
	Comments	Based on unstratified log-rank test. P-value is nominal p value without multiplicity adjustment.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.969
	Confidence Interval	(2-Sided) 95% 0.797 to 1.179
	Estimation Comments	Hazard Ratio is for Napabucasin + FOLFIRI ± bev vs FOLFIRI ± bev. Based on unstratified Cox proportional hazards model. A hazard ratio <1 indicates a lower risk with Napabucasin+ FOLFIRI ± bev compared with FOLFIRI ± bev.

2.Secondary Outcome


Title	Progression-Free Survival (PFS)
Description	PFS is defined as the time from randomization to the first objective d...
Description	PFS is defined as the time from randomization to the first objective documentation of disease progression per RECIST 1.1 (PD) or death, whichever comes first.
Time Frame	Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)

Outcome Measure Data

Analysis Population Description

The pSTAT3 subpopulations will be defined by the results of a Clinical Trial Assay (CTA) for a specimen with an age within a defined cut-section stability (CSS) window.


Arm/Group Title		Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description:		Napabucasin 240 mg will be administ...	Addition of bevacizumab to the FOLF...
Arm/Group Description:		Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion or at least 2 hours following the first daily dose of napabucasin if bevacizumab is not administered. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle.	Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle
Overall Number of Participants Analyzed		624	629
Median (95% Confidence Interval) Unit of Measure: months
Progression-Free Survival (PFS), General Population(GP)	Number Analyzed	624 participants	629 participants
Progression-Free Survival (PFS), General Population(GP)		5.55 (5.39 to 5.78)	5.62 (5.45 to 6.34)
Progression-Free Survival (PFS) , ITT-pSTAT3(+)	Number Analyzed	275 participants	272 participants
Progression-Free Survival (PFS) , ITT-pSTAT3(+)		5.39 (4.14 to 5.62)	5.55 (4.44 to 5.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	General population
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7307
	Comments	1-sided
	Method	Log Rank
	Comments	Based on stratified log rank test stratified by actual stratification factors . P-value is nominal p-value without multiplicity adjustment.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95% 0.917 to 1.180
	Estimation Comments	Based on Cox Proportional hazards model stratified by actual stratification . A HR <1 indicates a lower risk with Arm 1 compared with Arm 2.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	activated signal transducers and activators of transcription 3 (pSTAT3)-positive (pSTAT3(+)) Subpopulation patients
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7434
	Comments	1-sided
	Method	Log Rank
	Comments	Based on unstratified log-rank test. P-value is nominal p-value without multiplicity adjustment.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.064
	Confidence Interval	(2-Sided) 95% 0.883 to 1.283
	Estimation Comments	Hazard ratio is for Napabucasin + FOLFIRI ± bev vs FOLFIRI ± bev. Based on unstratified Cox Proportional hazards model. A hazard ratio <1 indicates a lower risk with Napabucasin + FOLFIRI ± bev compared with FOLFIRI ± bev.

3.Secondary Outcome


Title	Disease Control Rate (DCR)
Description	DCR is defined as the percentage of patients with a documented complet...
Description	DCR is defined as the percentage of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1. The primary estimate of DCR will be based on patients with measurable disease by RECIST 1.1 at randomization
Time Frame	Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)

Outcome Measure Data

Analysis Population Description

Analysis population of DCR will be based on patients with measurable disease by RECIST 1.1 at randomization. A patient with positive pSTAT3 status within a defined CSS window is the one with pSTAT3 positive designated by CTA with specimen age up to 6 months at interim analysis or up to the final CSS window at final analysis.


Arm/Group Title		Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description:		Napabucasin 240 mg will be administ...	Addition of bevacizumab to the FOLF...
Arm/Group Description:		Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle. Analysis population of DCR will be based on patients with measurable disease by RECIST 1.1 at randomization.	Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle. Analysis population of DCR will be based on patients with measurable disease by RECIST 1.1 at randomization.
Overall Number of Participants Analyzed		593	609
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
Disease Control Rate (DCR), General Population(GP)	Number Analyzed	593 participants	609 participants
Disease Control Rate (DCR), General Population(GP)		69.6 (65.8 to 73.3)	69.1 (65.3 to 72.8)
Disease Control Rate (DCR), ITT-pSTAT3(+)	Number Analyzed	268 participants	266 participants
Disease Control Rate (DCR), ITT-pSTAT3(+)		67.2 (61.2 to 72.8)	70.3 (64.4 to 75.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	General population
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4797
	Comments	1-sided
	Method	Cochran-Mantel-Haenszel
	Comments	Based on Cochran-Mantel-Haenszel test stratified by actual stratification factors. P-value is nominal p-value without multiplicity adjustment .

Method of Estimation	Estimation Parameter	rate difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95% -4.9 to 5.2
	Estimation Comments	Treatment difference and 95% CI is based on Harmonic Means method adjusting stratification factor

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	activated signal transducers and activators of transcription 3 (pSTAT3)-positive (pSTAT3(+)) Subpopulation patients
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.783
	Comments	1-sided
	Method	Z test
	Comments	Based on one-sided Z test. P-value is nominal p-value without multiplicity adjustment.

Method of Estimation	Estimation Parameter	rate difference
	Estimated Value	-3.1
	Confidence Interval	(2-Sided) 95% -11.0 to 4.7
	Estimation Comments	Treatment difference and 95% CI is based on normal approximation method.

4.Secondary Outcome


Title	Objective Response Rate (ORR)
Description	ORR is defined as the proportion of patients with a documented complet...
Description	ORR is defined as the proportion of patients with a documented complete response and partial response (CR + PR) based on RECIST 1.1. The primary estimate for ORR will be based on patients with measurable disease by RECIST 1.1 at randomization.
Time Frame	Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)

Outcome Measure Data

Analysis Population Description

Analysis set for ORR will be based on patients with measurable disease by RECIST 1.1 at randomization.


Arm/Group Title		Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description:		Napabucasin 240 mg will be administ...	Addition of bevacizumab to the FOLF...
Arm/Group Description:		Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle. Analysis set for ORR will be based on patients with measurable disease by RECIST 1.1 at randomization.	Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle. Analysis set for ORR will be based on patients with measurable disease by RECIST 1.1 at randomization.
Overall Number of Participants Analyzed		593	609
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
Objective Response Rate (ORR), General Population(GP)	Number Analyzed	593 participants	609 participants
Objective Response Rate (ORR), General Population(GP)		13.8 (11.2 to 16.9)	14.6 (11.9 to 17.7)
Objective Response Rate (ORR), ITT-pSTAT3(+)	Number Analyzed	268 participants	266 participants
Objective Response Rate (ORR), ITT-pSTAT3(+)		11.9 (8.3 to 16.4)	13.9 (10.0 to 18.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	General population
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6776
	Comments	1-sided
	Method	Cochran-Mantel-Haenszel
	Comments	Based on Cochran-Mantel-Haenszel test stratified by actual stratification factors. P-value is nominal p-value without multiplicity adjustment.

Method of Estimation	Estimation Parameter	rate difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95% -4.8 to 3.0
	Estimation Comments	Treatment difference and 95% CI is based on Harmonic Means method adjusting stratification factor

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	activated signal transducers and activators of transcription 3 (pSTAT3)-positive (pSTAT3(+)) Subpopulation patients
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7513
	Comments	1-sided
	Method	Z test
	Comments	Based on one-sided Z test. P-value is nominal p-value without multiplicity adjustment.

Method of Estimation	Estimation Parameter	rate difference
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95% -7.7 to 3.7
	Estimation Comments	Treatment difference and 95% CI is based on normal approximation method.

5.Secondary Outcome


Title	Mean Change From Baseline for Global Health Status at Time 2 (Cycle 5 Day 1) and Time 4 (Cycle 9 Day 1).
Description	The Quality of Life (QoL) of patients will be assessed using European ...
Description	The Quality of Life (QoL) of patients will be assessed using European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ-C30) (EORTC QLQ-30) while the patient remains on study treatment (FOLFIRI with or without BBI-608). EORTC QLQ-30 is used to assess the overall quality of life in cancer patients using 28 questions with a 4 point scale. (1 'Not at all' to 4'Very Much'); 2 questions use a 7-point sale (1 'Very Poor' to 7 'Excellent'). Scores are averaged and transformed to 0-100 scale; higher overall score = better quality of life.
Time Frame	From baseline at Time 2 (Cycle 5 Day 1), approximately 57 days and Time 4 (Cycle 9 Day 1), approximately 113 days

Outcome Measure Data

Analysis Population Description

The number of patients is with at least one valid assessment at each analysis window


Arm/Group Title		Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description:		Napabucasin 240 mg will be administ...	Addition of bevacizumab to the FOLF...
Arm/Group Description:		Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle. Number of patients is with at least one valid assessment at each analysis window.	Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle. Number of patients is with at least one valid assessment at each analysis window.
Overall Number of Participants Analyzed		622	626
Mean (Standard Deviation) Unit of Measure: score on a scale
Mean Change From Baseline for Global Health status at Time 2 (Cycle 5 Day 1). General Population	Number Analyzed	376 participants	341 participants
		-7.07 (21.936)	-5.45 (20.607)
Mean Change From Baseline for Global Health status at Time 4 (Cycle 9 Day 1). General Population	Number Analyzed	370 participants	360 participants
		-7.70 (21.932)	-5.58 (21.590)

6.Secondary Outcome


Title	Mean Change From Baseline for Physical Functioning Status at Time 2 (Cycle 5 Day 1) and Time 4 (Cycle 9 Day 1).
Description	The Quality of Life (QoL) of patients will be assessed using European ...
Description	The Quality of Life (QoL) of patients will be assessed using European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ-C30) (EORTC QLQ-30) while the patient remains on study treatment (FOLFIRI with or without BBI-608). EORTC QLQ-30 is used to assess the overall quality of life in cancer patients using 28 questions with a 4 point scale. (1 'Not at all' to 4'Very Much'); 2 questions use a 7-point sale (1 'Very Poor' to 7 'Excellent'). Scores are averaged and transformed to 0-100 scale; higher overall score = better quality of life.
Time Frame	From baseline at Time 2 (Cycle 5 Day 1) and Time 4 (Cycle 9 Day 1)

Outcome Measure Data

Analysis Population Description

The number of patients is with at least one valid assessment at each analysis window.


Arm/Group Title		Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description:		Napabucasin 240 mg will be administ...	Addition of bevacizumab to the FOLF...
Arm/Group Description:		Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle. Number of patients is with at least one valid assessment at each analysis window.	Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle. Number of patients is with at least one valid assessment at each analysis window.
Overall Number of Participants Analyzed		622	626
Mean (Standard Deviation) Unit of Measure: QOL score on a scale
Mean Change From Baseline for Physical Functioning at Time 2 (Cycle 5 Day 1). General Population	Number Analyzed	375 participants	343 participants
		-5.86 (17.204)	-3.94 (14.472)
Mean Change From Baseline for Physical Functioning at Time 4 (Cycle 9 Day 1). General Population	Number Analyzed	369 participants	363 participants
		-6.37 (15.095)	-4.22 (15.023)

7.Secondary Outcome


Title	Number of Patients With Adverse Events in the General Population
Description	All patients who have received at least one dose of either BBI-608 or ...
Description	All patients who have received at least one dose of either BBI-608 or FOLFIRI will be included in the safety analysis according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.0. The incidence of adverse events will be summarized by type of adverse event and severity.
Time Frame	All adverse event are collected from date of signed informed consent until 30 days after protocol treatment discontinuation. Outcome followed until study discontinuation up to 4 years

Outcome Measure Data

Analysis Population Description

All patients who received at least 1 dose of study drug (BBI-608 and/or FOLFIRI) with treatment assignment designated according to the actual study treatment received. Adverse event is analyzed in the SAS population.


Arm/Group Title		Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description:		All patients who received at least ...	All patients who received at least ...
Arm/Group Description:		All patients who received at least 1 dose of study drug (BBI-608 and/or FOLFIRI) with treatment assignment designated according to the actual study treatment received. Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). This regimen will be repeated on Day 1 of every 14 day cycle.	All patients who received at least 1 dose of study drug (FOLFIRI) with treatment assignment designated according to the actual study treatment received. Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). This regimen will be repeated on Day 1 of every 14 day cycle.
Overall Number of Participants Analyzed		622	610
Measure Type: Count of Participants Unit of Measure: Participants
Number of Patients with Adverse Events in the General Population	Number Analyzed	622 participants	610 participants
		619 99.5%	602 98.7%
Number of Patients with Adverse Events in the pSTAT3(+) Subpopulation	Number Analyzed	275 participants	269 participants
		275 100.0%	266 98.9%

Adverse Events

Time Frame	All adverse event are collected from date of signed informed consent until 30 days after protocol treatment discontinuation. Outcome followed until study discontinuation.
Adverse Event Reporting Description	All adverse event are collected from date of signed informed consent until 30 days after protocol treatment discontinuation. Outcome followed until study discontinuation up to 4 years. All cause mortality is analyzed in the ITT population. That's why total number of participants at risk in the ITT population (624 Arm A, 629 Arm B) appears inconsistent with total number of participants at risk in the adverse event analysis in the SAS population (622 Arm A, 610 Arm B)

Arm/Group Title	Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
Arm/Group Description	All patients who received at least ...	All patients who received at least ...
Arm/Group Description	All patients who received at least 1 dose of study drug (BBI-608 and/or FOLFIRI) with treatment assignment designated according to the actual study treatment received. Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). This regimen will be repeated on Day 1 of every 14 day cycle.	All patients who received at least 1 dose of study drug (BBI-608 and/or FOLFIRI) with treatment assignment designated according to the actual study treatment received. Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). This regimen will be repeated on Day 1 of every 14 day cycle.
All-Cause Mortality
	Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	507/624 (81.25%)	499/629 (79.33%)
Serious Adverse Events Serious Adverse Events
	Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	234/622 (37.62%)	201/610 (32.95%)
Blood and lymphatic system disorders
Anaemia ^† 1	9/622 (1.45%)	4/610 (0.66%)
Febrile Neutropenia ^† 1	8/622 (1.29%)	12/610 (1.97%)
Neutropenia ^† 1	4/622 (0.64%)	3/610 (0.49%)
Thrombocytopenia ^† 1	3/622 (0.48%)	2/610 (0.33%)
Pancytopenia ^† 1	2/622 (0.32%)	0/610 (0.00%)
Bone Marrow Failure ^† 1	1/622 (0.16%)	1/610 (0.16%)
Disseminated Intravascular Coagulation ^† 1	1/622 (0.16%)	0/610 (0.00%)
Leukopenia ^† 1	1/622 (0.16%)	1/610 (0.16%)
Thrombocytosis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Cardiac disorders
Atrial Fibrillation ^† 1	3/622 (0.48%)	4/610 (0.66%)
Acute Coronary Syndrome ^† 1	1/622 (0.16%)	0/610 (0.00%)
Acute Myocardial Infarction ^† 1	1/622 (0.16%)	1/610 (0.16%)
Atrial Flutter ^† 1	1/622 (0.16%)	1/610 (0.16%)
Cardiac Arrest ^† 1	1/622 (0.16%)	1/610 (0.16%)
Cardiac Failure ^† 1	1/622 (0.16%)	0/610 (0.00%)
Tachycardia ^† 1	1/622 (0.16%)	0/610 (0.00%)
Ventricular Fibrillation ^† 1	1/622 (0.16%)	0/610 (0.00%)
Myocardial Infarction ^† 1	0/622 (0.00%)	1/610 (0.16%)
Myocarditis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Gastrointestinal disorders
Diarrhoea ^† 1	39/622 (6.27%)	19/610 (3.11%)
Abdominal Pain ^† 1	17/622 (2.73%)	16/610 (2.62%)
Intestinal Obstruction ^† 1	10/622 (1.61%)	15/610 (2.46%)
Small Intestinal Obstruction ^† 1	10/622 (1.61%)	12/610 (1.97%)
Vomiting ^† 1	10/622 (1.61%)	8/610 (1.31%)
Nausea ^† 1	9/622 (1.45%)	4/610 (0.66%)
Ileus ^† 1	4/622 (0.64%)	8/610 (1.31%)
Ascites ^† 1	3/622 (0.48%)	3/610 (0.49%)
Intestinal Perforation ^† 1	3/622 (0.48%)	2/610 (0.33%)
Large Intestinal Obstruction ^† 1	3/622 (0.48%)	4/610 (0.66%)
Upper Gastrointestinal Haemorrhage ^† 1	3/622 (0.48%)	1/610 (0.16%)
Colitis ^† 1	2/622 (0.32%)	3/610 (0.49%)
Enterocolitis ^† 1	2/622 (0.32%)	0/610 (0.00%)
Lower Gastrointestinal Haemorrhage ^† 1	2/622 (0.32%)	1/610 (0.16%)
Oesophageal Varices Haemorrhage ^† 1	2/622 (0.32%)	0/610 (0.00%)
Pancreatitis ^† 1	2/622 (0.32%)	0/610 (0.00%)
Rectal Haemorrhage ^† 1	2/622 (0.32%)	1/610 (0.16%)
Abdominal Hernia Obstructive ^† 1	1/622 (0.16%)	0/610 (0.00%)
Diarrhoea Haemorrhagic ^† 1	1/622 (0.16%)	0/610 (0.00%)
Duodenal Ulcer Haemorrhage ^† 1	1/622 (0.16%)	0/610 (0.00%)
Enteritis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Gastrointestinal Disorder ^† 1	1/622 (0.16%)	0/610 (0.00%)
Gastrointestinal Haemorrhage ^† 1	1/622 (0.16%)	1/610 (0.16%)
Gastrointestinal Inflammation ^† 1	1/622 (0.16%)	1/610 (0.16%)
Gastrointestinal Perforation ^† 1	1/622 (0.16%)	0/610 (0.00%)
Gastrointestinal Toxicity ^† 1	1/622 (0.16%)	0/610 (0.00%)
Haematochezia ^† 1	1/622 (0.16%)	1/610 (0.16%)
Haemorrhoidal Haemorrhage ^† 1	1/622 (0.16%)	0/610 (0.00%)
Haemorrhoids ^† 1	1/622 (0.16%)	0/610 (0.00%)
Inguinal Hernia Strangulated ^† 1	1/622 (0.16%)	0/610 (0.00%)
Large Intestinal Stenosis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Melaena ^† 1	1/622 (0.16%)	0/610 (0.00%)
Obstruction Gastric ^† 1	1/622 (0.16%)	1/610 (0.16%)
Pancreatitis Acute ^† 1	1/622 (0.16%)	0/610 (0.00%)
Pneumoperitoneum ^† 1	1/622 (0.16%)	0/610 (0.00%)
Proctalgia ^† 1	1/622 (0.16%)	0/610 (0.00%)
Abdominal Distension ^† 1	0/622 (0.00%)	1/610 (0.16%)
Colitis Ischaemic ^† 1	0/622 (0.00%)	2/610 (0.33%)
Constipation ^† 1	0/622 (0.00%)	1/610 (0.16%)
Duodenal Perforation ^† 1	0/622 (0.00%)	1/610 (0.16%)
Gastric Ulcer Perforation ^† 1	0/622 (0.00%)	1/610 (0.16%)
Inguinal Hernia ^† 1	0/622 (0.00%)	1/610 (0.16%)
Large Intestine Perforation ^† 1	0/622 (0.00%)	1/610 (0.16%)
Mouth Ulceration ^† 1	0/622 (0.00%)	1/610 (0.16%)
Pneumatosis Intestinalis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Stomatitis ^† 1	0/622 (0.00%)	2/610 (0.33%)
Subileus ^† 1	0/622 (0.00%)	1/610 (0.16%)
Toothache ^† 1	0/622 (0.00%)	1/610 (0.16%)
General disorders
Pyrexia ^† 1	18/622 (2.89%)	16/610 (2.62%)
Disease Progression ^† 1	17/622 (2.73%)	15/610 (2.46%)
General Physical Health Deterioration ^† 1	5/622 (0.80%)	5/610 (0.82%)
Asthenia ^† 1	4/622 (0.64%)	4/610 (0.66%)
Fatigue ^† 1	4/622 (0.64%)	2/610 (0.33%)
Death ^† 1	2/622 (0.32%)	1/610 (0.16%)
Mucosal Inflammation ^† 1	2/622 (0.32%)	1/610 (0.16%)
Non-Cardiac Chest Pain ^† 1	2/622 (0.32%)	1/610 (0.16%)
Chills ^† 1	1/622 (0.16%)	0/610 (0.00%)
Malaise ^† 1	1/622 (0.16%)	1/610 (0.16%)
Mucosal Toxicity ^† 1	1/622 (0.16%)	0/610 (0.00%)
Oedema Peripheral ^† 1	1/622 (0.16%)	2/610 (0.33%)
Pain ^† 1	1/622 (0.16%)	0/610 (0.00%)
Inflammation ^† 1	0/622 (0.00%)	1/610 (0.16%)
Hepatobiliary disorders
Hyperbilirubinaemia ^† 1	3/622 (0.48%)	1/610 (0.16%)
Bile Duct Obstruction ^† 1	2/622 (0.32%)	1/610 (0.16%)
Cholangitis ^† 1	2/622 (0.32%)	0/610 (0.00%)
Cholecystitis Acute ^† 1	2/622 (0.32%)	1/610 (0.16%)
Cholecystitis ^† 1	1/622 (0.16%)	1/610 (0.16%)
Gallbladder Necrosis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Hepatic Function Abnormal ^† 1	1/622 (0.16%)	0/610 (0.00%)
Jaundice Cholestatic ^† 1	1/622 (0.16%)	1/610 (0.16%)
Bile Duct Stenosis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Cholelithiasis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Liver Injury ^† 1	0/622 (0.00%)	1/610 (0.16%)
Immune system disorders
Drug Hypersensitivity ^† 1	1/622 (0.16%)	0/610 (0.00%)
Anaphylactic Reaction ^† 1	0/622 (0.00%)	2/610 (0.33%)
Infections and infestations
Sepsis ^† 1	7/622 (1.13%)	10/610 (1.64%)
Urinary Tract Infection ^† 1	6/622 (0.96%)	0/610 (0.00%)
Pneumonia ^† 1	4/622 (0.64%)	8/610 (1.31%)
Anal Abscess ^† 1	2/622 (0.32%)	0/610 (0.00%)
Bacteraemia ^† 1	2/622 (0.32%)	2/610 (0.33%)
Clostridium Difficile Colitis ^† 1	2/622 (0.32%)	1/610 (0.16%)
Infection ^† 1	2/622 (0.32%)	1/610 (0.16%)
Abdominal Infection ^† 1	1/622 (0.16%)	0/610 (0.00%)
Abdominal Sepsis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Appendicitis Perforated ^† 1	1/622 (0.16%)	0/610 (0.00%)
Bacterial Sepsis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Cellulitis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Clostridium Difficile Infection ^† 1	1/622 (0.16%)	0/610 (0.00%)
Colonic Abscess ^† 1	1/622 (0.16%)	0/610 (0.00%)
Device Related Infection ^† 1	1/622 (0.16%)	1/610 (0.16%)
Diverticulitis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Empyema ^† 1	1/622 (0.16%)	0/610 (0.00%)
Enterocolitis Infectious ^† 1	1/622 (0.16%)	0/610 (0.00%)
Herpes Zoster ^† 1	1/622 (0.16%)	0/610 (0.00%)
Infected Dermal Cyst ^† 1	1/622 (0.16%)	0/610 (0.00%)
Lung Infection ^† 1	1/622 (0.16%)	0/610 (0.00%)
Nosocomial Infection ^† 1	1/622 (0.16%)	0/610 (0.00%)
Perirectal Abscess ^† 1	1/622 (0.16%)	0/610 (0.00%)
Peritonitis ^† 1	1/622 (0.16%)	1/610 (0.16%)
Peritonsillar Abscess ^† 1	1/622 (0.16%)	0/610 (0.00%)
Pneumonia Influenzal ^† 1	1/622 (0.16%)	0/610 (0.00%)
Pseudomonas Bronchitis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Rectal Abscess ^† 1	1/622 (0.16%)	0/610 (0.00%)
Retroperitoneal Abscess ^† 1	1/622 (0.16%)	0/610 (0.00%)
Septic Shock ^† 1	1/622 (0.16%)	4/610 (0.66%)
Urinary Tract Infection ^† 1	1/622 (0.16%)	0/610 (0.00%)
Urosepsis ^† 1	1/622 (0.16%)	1/610 (0.16%)
Viral Infection ^† 1	1/622 (0.16%)	0/610 (0.00%)
Abdominal Abscess ^† 1	0/622 (0.00%)	1/610 (0.16%)
Abdominal Wall Abscess ^† 1	0/622 (0.00%)	1/610 (0.16%)
Abscess Jaw ^† 1	0/622 (0.00%)	1/610 (0.16%)
Abscess Rupture ^† 1	0/622 (0.00%)	1/610 (0.16%)
Anorectal Infection ^† 1	0/622 (0.00%)	1/610 (0.16%)
Bronchitis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Coccidioidomycosis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Community Acquired ^† 1	0/622 (0.00%)	1/610 (0.16%)
Cystitis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Endocarditis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Epididymitis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Fungal Sepsis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Lower Respiratory Tract Infection ^† 1	0/622 (0.00%)	1/610 (0.16%)
Necrotising Fasciitis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Ophthalmic Herpes Zoster ^† 1	0/622 (0.00%)	1/610 (0.16%)
Pelvic Abscess ^† 1	0/622 (0.00%)	1/610 (0.16%)
Pelvic Infection ^† 1	0/622 (0.00%)	1/610 (0.16%)
Pharyngitis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Pneumonia Pneumococcal ^† 1	0/622 (0.00%)	1/610 (0.16%)
Psoas Abscess ^† 1	0/622 (0.00%)	1/610 (0.16%)
Pulmonary Sepsis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Pyelonephritis ^† 1	0/622 (0.00%)	4/610 (0.66%)
Pyonephrosis ^† 1	0/622 (0.00%)	1/610 (0.16%)
Respiratory Tract ^† 1	0/622 (0.00%)	1/610 (0.16%)
Streptococcal Bacteraemia ^† 1	0/622 (0.00%)	1/610 (0.16%)
Injury, poisoning and procedural complications
Accidental Overdose ^† 1	2/622 (0.32%)	0/610 (0.00%)
Ankle Fracture ^† 1	2/622 (0.32%)	0/610 (0.00%)
Hip Fracture ^† 1	2/622 (0.32%)	1/610 (0.16%)
Infusion Related Reaction ^† 1	2/622 (0.32%)	0/610 (0.00%)
Spinal Fracture ^† 1	2/622 (0.32%)	0/610 (0.00%)
Stoma Site Haemorrhage ^† 1	2/622 (0.32%)	3/610 (0.49%)
Femoral Neck Fracture ^† 1	1/622 (0.16%)	0/610 (0.00%)
Femur Fracture ^† 1	1/622 (0.16%)	0/610 (0.00%)
Gastrointestinal Stoma Complication ^† 1	1/622 (0.16%)	1/610 (0.16%)
Lumbar Vertebral Fracture ^† 1	1/622 (0.16%)	1/610 (0.16%)
Road Traffic Accident ^† 1	1/622 (0.16%)	0/610 (0.00%)
Stoma Complication ^† 1	1/622 (0.16%)	0/610 (0.00%)
Overdose ^† 1	0/622 (0.00%)	1/610 (0.16%)
Subdural Haematoma ^† 1	0/622 (0.00%)	1/610 (0.16%)
Investigations
Blood Bilirubin Increased ^† 1	2/622 (0.32%)	1/610 (0.16%)
Neutrophil Count Decreased ^† 1	2/622 (0.32%)	8/610 (1.31%)
Platelet Count Decreased ^† 1	2/622 (0.32%)	1/610 (0.16%)
Alanine Aminotransferase Increased ^† 1	1/622 (0.16%)	0/610 (0.00%)
Aspartate Aminotransferase Increased ^† 1	1/622 (0.16%)	0/610 (0.00%)
Myocardial Necrosis Marker Increased ^† 1	1/622 (0.16%)	0/610 (0.00%)
Red Blood Cell Count Decreased ^† 1	1/622 (0.16%)	0/610 (0.00%)
Blood Uric Acid Increased ^† 1	0/622 (0.00%)	1/610 (0.16%)
White Blood Cell Count Decreased ^† 1	0/622 (0.00%)	2/610 (0.33%)
Metabolism and nutrition disorders
Dehydration ^† 1	15/622 (2.41%)	9/610 (1.48%)
Hypokalaemia ^† 1	5/622 (0.80%)	6/610 (0.98%)
Decreased Appetite ^† 1	4/622 (0.64%)	3/610 (0.49%)
Failure To Thrive ^† 1	1/622 (0.16%)	1/610 (0.16%)
Hyperglycaemia ^† 1	1/622 (0.16%)	0/610 (0.00%)
Hyperkalaemia ^† 1	1/622 (0.16%)	0/610 (0.00%)
Hypoglycaemia ^† 1	1/622 (0.16%)	0/610 (0.00%)
Hyponatraemia ^† 1	1/622 (0.16%)	0/610 (0.00%)
Hypovolaemia ^† 1	1/622 (0.16%)	0/610 (0.00%)
Hypophagia ^† 1	0/622 (0.00%)	1/610 (0.16%)
Musculoskeletal and connective tissue disorders
Back Pain ^† 1	3/622 (0.48%)	4/610 (0.66%)
Muscular Weakness ^† 1	1/622 (0.16%)	0/610 (0.00%)
Myopathy ^† 1	1/622 (0.16%)	0/610 (0.00%)
Pain In Extremity ^† 1	1/622 (0.16%)	0/610 (0.00%)
Fracture Pain ^† 1	0/622 (0.00%)	1/610 (0.16%)
Osteonecrosis Of Jaw ^† 1	0/622 (0.00%)	1/610 (0.16%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant Ascites ^† 1	1/622 (0.16%)	0/610 (0.00%)
Metastases To Kidney ^† 1	1/622 (0.16%)	0/610 (0.00%)
Metastases To Liver ^† 1	1/622 (0.16%)	0/610 (0.00%)
Metastases To Lung ^† 1	1/622 (0.16%)	0/610 (0.00%)
Pituitary Tumour Benign ^† 1	1/622 (0.16%)	0/610 (0.00%)
Tumour Haemorrhage ^† 1	1/622 (0.16%)	0/610 (0.00%)
Colon Cancer Metastatic ^† 1	0/622 (0.00%)	1/610 (0.16%)
Metastases To Heart ^† 1	0/622 (0.00%)	1/610 (0.16%)
Metastases To Peritoneum ^† 1	0/622 (0.00%)	1/610 (0.16%)
Tumour Pain ^† 1	0/622 (0.00%)	1/610 (0.16%)
Nervous system disorders
Syncope ^† 1	2/622 (0.32%)	3/610 (0.49%)
Altered State Of Consciousness ^† 1	1/622 (0.16%)	0/610 (0.00%)
Cerebral Infarction ^† 1	1/622 (0.16%)	0/610 (0.00%)
Presyncope ^† 1	1/622 (0.16%)	0/610 (0.00%)
Subarachnoid Haemorrhage ^† 1	1/622 (0.16%)	0/610 (0.00%)
Superior Sagittal Sinus Thrombosis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Transient Ischaemic Attack ^† 1	1/622 (0.16%)	0/610 (0.00%)
Encephalopathy ^† 1	0/622 (0.00%)	1/610 (0.16%)
Seizure ^† 1	0/622 (0.00%)	1/610 (0.16%)
Spinal Cord Compression ^† 1	0/622 (0.00%)	1/610 (0.16%)
Spinal Cord Disorder ^† 1	0/622 (0.00%)	1/610 (0.16%)
Product Issues
Device Dislocation ^† 1	1/622 (0.16%)	0/610 (0.00%)
Thrombosis In Device ^† 1	1/622 (0.16%)	0/610 (0.00%)
Psychiatric disorders
Confusional State ^† 1	1/622 (0.16%)	0/610 (0.00%)
Hallucination ^† 1	1/622 (0.16%)	0/610 (0.00%)
Mental Status Changes ^† 1	1/622 (0.16%)	0/610 (0.00%)
Aggression ^† 1	0/622 (0.00%)	1/610 (0.16%)
Anxiety ^† 1	0/622 (0.00%)	1/610 (0.16%)
Renal and urinary disorders
Acute Kidney Injury ^† 1	7/622 (1.13%)	3/610 (0.49%)
Acute Prerenal Failure ^† 1	1/622 (0.16%)	0/610 (0.00%)
Haematuria ^† 1	1/622 (0.16%)	1/610 (0.16%)
Prerenal Failure ^† 1	1/622 (0.16%)	0/610 (0.00%)
Renal Impairment ^† 1	1/622 (0.16%)	0/610 (0.00%)
Ureterolithiasis ^† 1	1/622 (0.16%)	1/610 (0.16%)
Hydronephrosis ^† 1	0/622 (0.00%)	2/610 (0.33%)
Hydroureter ^† 1	0/622 (0.00%)	1/610 (0.16%)
Urinary Retention ^† 1	0/622 (0.00%)	2/610 (0.33%)
Urinary Tract Obstruction ^† 1	0/622 (0.00%)	2/610 (0.33%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism ^† 1	12/622 (1.93%)	9/610 (1.48%)
Pleural Effusion ^† 1	5/622 (0.80%)	2/610 (0.33%)
Dyspnoea ^† 1	3/622 (0.48%)	1/610 (0.16%)
Pneumonitis ^† 1	2/622 (0.32%)	0/610 (0.00%)
Respiratory Failure ^† 1	2/622 (0.32%)	2/610 (0.33%)
Aspiration ^† 1	1/622 (0.16%)	0/610 (0.00%)
Chronic Obstructive Pulmonary Disease ^† 1	1/622 (0.16%)	0/610 (0.00%)
Interstitial Lung Disease ^† 1	1/622 (0.16%)	1/610 (0.16%)
Lung Infiltration ^† 1	1/622 (0.16%)	0/610 (0.00%)
Pneumothorax ^† 1	1/622 (0.16%)	0/610 (0.00%)
Pulmonary Artery Thrombosis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Pulmonary Oedema ^† 1	0/622 (0.00%)	1/610 (0.16%)
Surgical and medical procedures
Tumour Excision ^† 1	1/622 (0.16%)	0/610 (0.00%)
Vascular disorders
Hypotension ^† 1	6/622 (0.96%)	3/610 (0.49%)
Deep Vein Thrombosis ^† 1	2/622 (0.32%)	2/610 (0.33%)
Embolism ^† 1	2/622 (0.32%)	1/610 (0.16%)
Haemorrhage ^† 1	1/622 (0.16%)	0/610 (0.00%)
Hypovolaemic Shock ^† 1	1/622 (0.16%)	0/610 (0.00%)
Orthostatic Hypotension ^† 1	1/622 (0.16%)	1/610 (0.16%)
Subclavian Vein Thrombosis ^† 1	1/622 (0.16%)	0/610 (0.00%)
Venous Thrombosis ^† 1	0/622 (0.00%)	1/610 (0.16%)
1 Term from vocabulary, MedDRA 19.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	619/622 (99.52%)	602/610 (98.69%)
Blood and lymphatic system disorders
Anaemia ^† 1	154/622 (24.76%)	148/610 (24.26%)
Neutropenia ^† 1	154/622 (24.76%)	165/610 (27.05%)
Thrombocytopenia ^† 1	36/622 (5.79%)	24/610 (3.93%)
Leukopenia ^† 1	32/622 (5.14%)	43/610 (7.05%)
Gastrointestinal disorders
Diarrhoea ^† 1	526/622 (84.57%)	329/610 (53.93%)
Nausea ^† 1	376/622 (60.45%)	308/610 (50.49%)
Vomiting ^† 1	256/622 (41.16%)	180/610 (29.51%)
Abdominal Pain ^† 1	255/622 (41.00%)	154/610 (25.25%)
Constipation ^† 1	126/622 (20.26%)	173/610 (28.36%)
Stomatitis ^† 1	92/622 (14.79%)	118/610 (19.34%)
Abdominal Pain Upper ^† 1	63/622 (10.13%)	46/610 (7.54%)
Dyspepsia ^† 1	56/622 (9.00%)	39/610 (6.39%)
Proctalgia ^† 1	35/622 (5.63%)	20/610 (3.28%)
Abdominal Distension ^† 1	34/622 (5.47%)	31/610 (5.08%)
General disorders
Fatigue ^† 1	235/622 (37.78%)	219/610 (35.90%)
Asthenia ^† 1	135/622 (21.70%)	119/610 (19.51%)
Pyrexia ^† 1	117/622 (18.81%)	100/610 (16.39%)
Mucosal Inflammation ^† 1	60/622 (9.65%)	90/610 (14.75%)
Oedema Peripheral ^† 1	45/622 (7.23%)	48/610 (7.87%)
Malaise ^† 1	43/622 (6.91%)	34/610 (5.57%)
Infections and infestations
Urinary Tract Infection ^† 1	71/622 (11.41%)	40/610 (6.56%)
Upper Respiratory Tract Infection ^† 1	44/622 (7.07%)	43/610 (7.05%)
Investigations
Neutrophil Count Decreased ^† 1	149/622 (23.95%)	179/610 (29.34%)
Weight Decreased ^† 1	106/622 (17.04%)	54/610 (8.85%)
White Blood Cell Count Decreased ^† 1	87/622 (13.99%)	109/610 (17.87%)
Aspartate Aminotransferase Increased ^† 1	75/622 (12.06%)	67/610 (10.98%)
Alanine Aminotransferase Increased ^† 1	67/622 (10.77%)	57/610 (9.34%)
Blood Alkaline Phosphatase Increased ^† 1	59/622 (9.49%)	35/610 (5.74%)
Platelet Count Decreased ^† 1	42/622 (6.75%)	47/610 (7.70%)
Blood Bilirubin Increased ^† 1	30/622 (4.82%)	32/610 (5.25%)
Metabolism and nutrition disorders
Decreased Appetite ^† 1	233/622 (37.46%)	189/610 (30.98%)
Hypokalaemia ^† 1	103/622 (16.56%)	57/610 (9.34%)
Dehydration ^† 1	57/622 (9.16%)	36/610 (5.90%)
Hypoalbuminaemia ^† 1	33/622 (5.31%)	29/610 (4.75%)
Musculoskeletal and connective tissue disorders
Back Pain ^† 1	75/622 (12.06%)	84/610 (13.77%)
Nervous system disorders
Headache ^† 1	85/622 (13.67%)	73/610 (11.97%)
Dizziness ^† 1	59/622 (9.49%)	47/610 (7.70%)
Dysgeusia ^† 1	46/622 (7.40%)	59/610 (9.67%)
Neuropathy Peripheral ^† 1	32/622 (5.14%)	22/610 (3.61%)
Cholinergic Syndrome ^† 1	20/622 (3.22%)	33/610 (5.41%)
Psychiatric disorders
Insomnia ^† 1	54/622 (8.68%)	84/610 (13.77%)
Renal and urinary disorders
Chromaturia ^† 1	70/622 (11.25%)	4/610 (0.66%)
Proteinuria ^† 1	54/622 (8.68%)	44/610 (7.21%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	72/622 (11.58%)	75/610 (12.30%)
Epistaxis ^† 1	60/622 (9.65%)	79/610 (12.95%)
Dyspnoea ^† 1	57/622 (9.16%)	46/610 (7.54%)
Hiccups ^† 1	41/622 (6.59%)	29/610 (4.75%)
Skin and subcutaneous tissue disorders
Alopecia ^† 1	133/622 (21.38%)	159/610 (26.07%)
Rash ^† 1	31/622 (4.98%)	41/610 (6.72%)
Palmar-Plantar Erythrodysaesthesia Syndrome ^† 1	30/622 (4.82%)	33/610 (5.41%)
Vascular disorders
Hypertension ^† 1	58/622 (9.32%)	65/610 (10.66%)
1 Term from vocabulary, MedDRA 19.0 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

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Name/Title:	Keiichi Saito
Organization:	Sumitomo Dainippon Pharma Oncology
Phone:	+1 (617)674-6800
EMail:	keiichi.saito@SDPOncology.com

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Responsible Party:	Sumitomo Pharma Oncology, Inc.
ClinicalTrials.gov Identifier:	NCT02753127
Other Study ID Numbers:	CanStem303C BB608-303CRC ( Other Identifier: Sumitomo Dainippon Pharma Oncology, Inc. ) 2016-001627-31 ( EudraCT Number )
First Submitted:	April 25, 2016
First Posted:	April 27, 2016
Results First Submitted:	October 26, 2021
Results First Posted:	April 26, 2022
Last Update Posted:	April 26, 2022

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