A Study of BBI608 in Combination With Standard Chemothera... | NCT02024607

Label	Type	Description	Intervention Names
ARM A- BBI608 in combination with FOLFOX6	Experimental	BBI608 is administered orally twice daily, continuously. Oxaliplatin 85 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2 over 46-48 hours) continuous intravenous infusion. This regimen will be repeated every 14 days thereafter.	Drug: BBI608 Drug: Fluorouracil Drug: Oxaliplatin Drug: Leucovorin
ARM B- BBI608 in combination with FOLFOX6 and Bevacizumab	Experimental	BBI608 is administered orally twice daily, continuously. Oxaliplatin 85 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2 over 46-48 hours) continuous intravenous infusion. Bevacizumab 5 mg/kg will be administered intravenously following oxaliplatin/leucovorin infusion. This regimen will be repeated every 14 days thereafter.	Drug: BBI608 Drug: Fluorouracil Drug: Oxaliplatin Drug: Leucovorin Drug: Bevacizumab
ARM C- BBI608 in combination with CAPOX	Experimental	BBI608 is administered orally twice daily, continuously. CAPOX regimen will be administered orally (capecitabine) and IV (oxaliplatin). Capecitabine 850 mg/m^2 will be administered orally twice-daily for 14 consecutive days and be repeated every 21 days. Oxaliplatin will be administered IV and be repeated every 21 days thereafter. If capecitabine is tolerated at the 850 mg/m^2 twice daily dose, dosage may be increased to 1000 mg/m^2 twice daily as tolerated after the first cycle.

Name	Type	Description	Arm Group Labels	Other Names
BBI608	Drug		ARM A- BBI608 in combination with FOLFOX6 ARM B- BBI608 in combination with FOLFOX6 and Bevacizumab ARM C- BBI608 in combination with CAPOX ARM D- BBI608 in combination with FOLFIRI

Measure	Description	Time Frame
Number of Participants With Adverse Events and Serious Adverse Events	Assessment of safety of napabucasin administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan in participants with advanced gastrointestinal malignancies by reporting of adverse events and serious adverse events	The time from the date of first treatment, while the patient is taking napabucasin, and for 30 days after stopping therapy, an average of 4 months.
The Objective Response Rate of Napabucasin Administered in Combination in FOLFIRI in Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer	Assessment of the objective response rate (ORR) of napabucasin administered in combination with FOLFIRI in patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer. The Objective Response Rate (ORR) is the proportion of participants with a complete response or partial response who have measurable disease at baseline imaging.	From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months

Measure	Description	Time Frame
Determination of the Maximum Observed Concentration (Cmax) and Area Under the Plasma Concentration vs. Time Curve (AUClast)	To determine the maximum concentration of napabucasin and the area under the plasma concentration vs. time curve of napabucasin when administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Signed written informed consent
A histologically confirmed solid tumor of the gastrointestinal tract including
1. Advanced unresectable, metastatic or recurrent colorectal carcinoma (CRC) for which treatment with FOLFOX6 with or without bevacizumab, FOLFIRI with or without bevacizumab, CAPOX, or regorafenib would be acceptable as determined by the Investigator. FOLFIRI/XELIRI-refractory patients with CRC enrolling on the FOLFIRI study arm must have failed treatment with one FOLFIRI pr XELIRI with or without bevacizumab regimen for unresectable or metastatic disease. Treatment failure is defined as progression of disease (clinical or radiologic) during treatment with FOLFIRI with or without bevacizumab or < 3 months after the last dose of treatment with FOLFIRI with or without bevacizumab. Patients with CRC enrolling on the regorafenib arm of this study will have previously received at least two previous lines of therapy for advanced colorectal cancer, and will have previously received treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Patients with K-ras wild type tumors enrolling on the regorafenib arm will also have previously received either cetuximab or panitumumab.
2. Hepatocellular carcinoma for which treatment with FOLFOX6 or CAPOX would be acceptable as determined by the Investigator.
3. Pancreatic adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI, or irinotecan would be acceptable as determined by the Investigator.
4. Cholangiocarcinoma for which treatment with FOLFOX6 or CAPOX would be acceptable as determined by the Investigator.
5. Gastric, GEJ or esophageal adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI, or irinotecan would be acceptable as determined by the Investigator.
Patients may be treatment naïve, or may have received standard chemotherapy; including regimens containing a fluoropyrimidine, or oxaliplatin, or irinotecan, or regorafenib, or bevacizumab.
≥18 years of age.
Karnofsky performance status score ≥70%.
Male or female patients of child-producing potential agree to use contraception or avoidance of pregnancy measures during the study and for 30 days after the last BBI608 dose.
Females of childbearing potential have a negative serum pregnancy test.
AST level ≤2.5 x ULN and ALT ≤ 2.5 × ULN. For patients with liver metastases, AST ≤3.5 x ULN, and AST ≤3.5 x ULN may be enrolled if agreed upon by the investigator and medical monitor for the sponsor.
Hemoglobin ≥10 g/dl.
Total bilirubin level ≤1.5 × ULN.
Creatinine ≤1.5 x ULN or creatinine clearance >60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (as determined by Cockcroft-Gault equation).
Absolute neutrophil count ≥ 1.5 x 10^9/L.
Platelets ≥100 x 10^9/L.
Life expectancy estimated at ≥3 months.

Exclusion Criteria:

Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 7 days of the first dose of BBI608.
Major surgery within 4 weeks prior to first dose.
Any known untreated brain metastases. Treated subjects must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated.
Pregnant or breastfeeding.
Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent
Unable or unwilling to swallow BBI608 capsules daily.
Prior treatment with BBI608.
Uncontrolled intercurrent illness
For patients to be treated with a regimen containing 5-fluorouracil/leucovorin:
1. Known hypersensitivity to 5-fluorouracil/leucovorin
2. Known dihydropyrimidine dehydrogenase (DPD) deficiency
For patients to be treated with a regimen containing capecitabine:
1. Known hypersensitivity to capecitabine
2. Known dihydropyrimidine dehydrogenase (DPD) deficiency
3. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent
For patients to be treated with a regimen containing oxaliplatin:
1. Neurosensory neuropathy ≥ grade 2 at baseline
2. Known hypersensitivity to oxaliplatin or other platinum containing compounds
For patients to be treated with a regimen containing irinotecan:
1. Known hypersensitivity to irinotecan
2. Abnormal glucuronidation of bilirubin
For patients to be treated with a regimen containing bevacizumab:
1. Current uncontrolled hypertension as well as prior history of hypertensive crisis or hypertensive encephalopathy
2. History of cardiac disease: congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina or cardiac arrhythmias requiring anti-arrhythmic therapy
3. History of arterial thrombotic or embolic events (within 6 months prior to study entry)
4. Significant vascular disease
5. Evidence of bleeding diathesis or clinically significant coagulopathy
6. Major surgical procedure within 28 days, or anticipation of the need for major surgical procedure during the course of the study as well as minor surgical procedure within 7 days prior to study enrollment
7. Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+.
8. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months
9. Ongoing serious, non-healing wound, ulcer, or bone fracture
10. Known hypersensitivity to any component of bevacizumab
11. History of reversible posterior leukoencephalopathy syndrome (RPLS)
For patients to be treated with a regimen containing regorafenib:
1. History of cardiac disease: congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina or cardiac arrhythmias requiring anti-arrhythmic therapy
2. Current uncontrolled hypertension
3. Interstitial lung disease with ongoing signs and symptoms at the time of screening
4. History of HIV infection or chronic hepatitis B or C
5. Active clinically serious infections
6. History of arterial or embolic events (within 6 months prior to study entry)
7. Liver cirrhosis ≥ Child-Pugh class B with uncontrolled ascites
8. History of RPLS
9. Ongoing serious, non-healing wound, ulcer, or bone fracture
10. Evidence of bleeding diathesis or a clinically significant coagulopathy
11. Renal failure requiring hemo- or peritoneal dialysis
12. Persistent proteinuria of CTCAE grade 3 (>3.5g/24 hours)
13. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent
14. Known hypersensitivity to regorafenib

Name	Affiliation	Role
Boston Biomedical	Sumitomo Pharma America, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic Campus in Arizona		Phoenix	Arizona	85054	United States
Florida Cancer Specialists

ID	Title	Description
FG000	Napabucasin Plus FOLFOX6	All participants who were enrolled to Arm A to receive napabucasin administered orally, twice daily, in combination with FOLFOX6 regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously starting on Day 1 of Cycle 1, after the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous intravenous (IV) infusion.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 23, 2017	Jul 23, 2021

Arm/Group Information

ID	Title	Description
BG000	Napabucasin Plus FOLFOX6	All participants who were enrolled to Arm A to receive napabucasin administered orally, twice daily, in combination with FOLFOX6 regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously starting on Day 1 of Cycle 1, after the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous intravenous (IV) infusion.
BG001	Napabucasin Plus FOLFOX6 Plus Bevacizumab	All participants who were enrolled to Arm B to receive napabucasin administered orally, twice daily, in combination with FOLFOX6 plus bevacizumab regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously over 2 hours starting on Day1 of Cycle 1, following the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous IV infusion. Bevacizumab 5 mg/kg was administered intravenously following the oxaliplatin/leucovorin infusion.
BG002	Napabucasin Plus CAPOX	All participants who were enrolled to Arm C to receive napabucasin administered orally, twice daily, in combination with CAPOX regimen. The CAPOX regimen was administered orally (capecitabine) and by IV (oxaliplatin). Starting on Day 1 of Cycle 1, capecitabine 850 mg/m2 was administered orally BID following the first daily dose of napabucasin for 14 consecutive days and repeated every 21 days. Oxaliplatin 130 mg/m2 was administered intravenously over 2 hours, following the first daily dose of napabucasin starting on Day 1 of Cycle 1 and repeated every 21 days thereafter. If capecitabine was tolerated at the 850 mg/m2 BID dose, the dosage could have been increased to 1000 mg/m2 BID as tolerated after the first cycle.
BG003	Napabucasin Plus FOLFIRI	All participants who were enrolled to Arm D to receive napabucasin administered orally, twice daily, in combination with FOLFIRI regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. This regimen was repeated every 14 days thereafter.
BG004	Napabucasin Plus FOLFIRI Plus Bevacizumab	All participants who were enrolled to Arm E to receive napabucasin administered orally, twice daily, in combination with FOLFIRI plus bevacizumab regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5 FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. Bevacizumab 5 mg/kg was administered intravenously following the irinotecan/leucovorin infusion. This regimen was repeated every 14 days thereafter.
BG005	Napabucasin Plus Regorafenib	All participants who were enrolled to Arm F to receive napabucasin administered orally, twice daily, in combination with regorafenib 120 mg, administered orally once daily with a low-fat meal, starting on Day 1 of Cycle 1 for 21 consecutive days of every 28 days thereafter. If regorafenib was tolerated in the first cycle, the dosage could have been increased to 160 mg once daily as tolerated after the first cycle.
BG006	Napabucasin Plus Irinotecan	All participants who were enrolled to Arm G to receive napabucasin administered orally, twice daily, in combination with irinotecan 180 mg/m2, administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. This regimen was repeated every 14 days thereafter.
BG007	Total	Total of all reporting groups

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Anticipated Posting Date

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Calculate Percentage

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Arm/Group Information

Denominators

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Analyses

Primary

Number of Participants With Adverse Events and Serious Adverse Events

Assessment of safety of napabucasin administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan in participants with advanced gastrointestinal malignancies by reporting of adverse events and serious adverse events

Posted

Count of Participants

Participants

The time from the date of first treatment, while the patient is taking napabucasin, and for 30 days after stopping therapy, an average of 4 months.

ID	Title	Description
OG000	Napabucasin Plus FOLFOX6	Napabucasin administered orally, twice daily, in combination with FOLFOX6 regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously starting on Day 1 of Cycle 1, after the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous intravenous (IV) infusion. Patients included in this group received at least one dose of study drug.
OG001	Napabucasin Plus FOLFOX6 Plus Bevacizumab	Napabucasin administered orally, twice daily, in combination with FOLFOX6 plus bevacizumab regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously over 2 hours starting on Day1 of Cycle 1, following the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous IV infusion. Bevacizumab 5 mg/kg was administered intravenously following the oxaliplatin/leucovorin infusion. Patients included in this group received at least one dose of study drug.
OG002	Napabucasin Plus CAPOX	Napabucasin administered orally, twice daily, in combination with CAPOX regimen. The CAPOX regimen was administered orally (capecitabine) and by IV (oxaliplatin). Starting on Day 1 of Cycle 1, capecitabine 850 mg/m2 was administered orally BID following the first daily dose of napabucasin for 14 consecutive days and repeated every 21 days. Oxaliplatin 130 mg/m2 was administered intravenously over 2 hours, following the first daily dose of napabucasin starting on Day 1 of Cycle 1 and repeated every 21 days thereafter. If capecitabine was tolerated at the 850 mg/m2 BID dose, the dosage could have been increased to 1000 mg/m2 BID as tolerated after the first cycle. Patients included in this group received at least one dose of study drug.
OG003	Napabucasin Plus FOLFIRI	Napabucasin administered orally, twice daily, in combination with FOLFIRI regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. This regimen was repeated every 14 days thereafter. Patients included in this group received at least one dose of study drug.
OG004	Napabucasin Plus FOLFIRI Plus Bevacizumab	Napabucasin administered orally, twice daily, in combination with FOLFIRI plus bevacizumab regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5 FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. Bevacizumab 5 mg/kg was administered intravenously following the irinotecan/leucovorin infusion. This regimen was repeated every 14 days thereafter. Patients included in this group received at least one dose of study drug.
OG005	Napabucasin Plus Regorafenib	Napabucasin administered orally, twice daily, in combination with regorafenib 120 mg, administered orally once daily with a low-fat meal, starting on Day 1 of Cycle 1 for 21 consecutive days of every 28 days thereafter. If regorafenib was tolerated in the first cycle, the dosage could have been increased to 160 mg once daily as tolerated after the first cycle. Patients included in this group received at least one dose of study drug.
OG006	Napabucasin Plus Irinotecan	Napabucasin administered orally, twice daily, in combination with irinotecan 180 mg/m2, administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. This regimen was repeated every 14 days thereafter. Patients included in this group received at least one dose of study drug.

Units	Counts
Participants	OG000115 OG00141 OG00287 OG003

Title

Denominators

Categories

Title	Measurements
	OG000115 OG00141 OG00287 OG003

Primary

The Objective Response Rate of Napabucasin Administered in Combination in FOLFIRI in Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer

Assessment of the objective response rate (ORR) of napabucasin administered in combination with FOLFIRI in patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer. The Objective Response Rate (ORR) is the proportion of participants with a complete response or partial response who have measurable disease at baseline imaging.

Analysis limited to a subset of group D in which patients had FOLFIRI/XELIRI refractory metastatic colorectal cancer. Patients in this subgroup also had a baseline scan and at least 1 disease assessment following the initiation of therapy.

Posted

Number

percentage of participants

From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months

ID	Title	Description
OG000	Napabucasin Plus FOLFIRI	Napabucasin administered orally, twice daily, in combination with FOLFIRI regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. This regimen was repeated every 14 days thereafter . Patients in this group had a baseline scan and at least one assessment approximately 8 weeks from baseline.

Secondary

Determination of the Maximum Observed Concentration (Cmax) and Area Under the Plasma Concentration vs. Time Curve (AUClast)

To determine the maximum concentration of napabucasin and the area under the plasma concentration vs. time curve of napabucasin when administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib.

Sponsor's decision to terminate further development of the napabucasin program. Data collection and analysis were therefore not conducted as planned.

Posted

Blood samples drawn on days 1, 2, 15, 16, 21, and 22 of the first study cycle

ID	Title	Description
OG000	Napabucasin Plus FOLFOX6	Napabucasin administered orally, twice daily, in combination with FOLFOX6 regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously starting on Day 1 of Cycle 1, after the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous intravenous (IV) infusion. Patients included in this group received at least one dose of study drug.
OG001	Napabucasin Plus FOLFOX6 Plus Bevacizumab	Napabucasin administered orally, twice daily, in combination with FOLFOX6 plus bevacizumab regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously over 2 hours starting on Day1 of Cycle 1, following the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous IV infusion. Bevacizumab 5 mg/kg was administered intravenously following the oxaliplatin/leucovorin infusion. Patients included in this group received at least one dose of study drug.

Secondary

Pharmacodynamics

To determine the response (increase or decrease) of biomarkers from biopsied tumors following the administration of napabucasin

No on-treatment biopsies were performed therefore no pharmacodynamic testing on tumor tissue was conducted.

Posted

Day 1 of cycle 2

ID	Title	Description
OG000	Napabucasin Plus FOLFOX6	All participants who were enrolled to Arm A to receive napabucasin administered orally, twice daily, in combination with FOLFOX6 regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously starting on Day 1 of Cycle 1, after the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous intravenous (IV) infusion.
OG001	Napabucasin Plus FOLFOX6 Plus Bevacizumab	All participants who were enrolled to Arm B to receive napabucasin administered orally, twice daily, in combination with FOLFOX6 plus bevacizumab regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously over 2 hours starting on Day1 of Cycle 1, following the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous IV infusion. Bevacizumab 5 mg/kg was administered intravenously following the oxaliplatin/leucovorin infusion.

Secondary

Disease Control Rate

To determine the anti-tumor activity (specifically the disease control rate) of napabucasin administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan. Percentage of participants with a documented complete response, partial response and stable disease based on RECIST 1.1.

Patients who received at least 1 cycle of study treatment and had at least 1 disease assessment following the initiation of therapy. Patients missing imaging assessment following the initiation of treatment are not included in the assessment for DCR.

Posted

Number

percentage of participants

From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months.

ID	Title	Description
OG000	Napabucasin Plus FOLFOX6	Napabucasin administered orally, twice daily, in combination with FOLFOX6 regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously starting on Day 1 of Cycle 1, after the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous intravenous (IV) infusion. Patients in this group had a baseline scan and at least one assessment approximately 8 weeks from baseline.
OG001	Napabucasin Plus FOLFOX6 Plus Bevacizumab

Secondary

Disease Control Rate of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer

To determine the disease control rate of napabucasin administered in combination with FOLFIRI in patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer. Percentage of participants with a documented complete response, partial response and stable disease based on RECIST 1.1.

Patients with FOLFIRI/XELIRI refractory metastatic colorectal cancer who received at least 1 cycle of study treatment and had at least 1 disease assessment following the initiation of therapy. Patients missing imaging assessment following the initiation of treatment are not included in the assessment for DCR.

Posted

Number

percentage of participants

From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months

ID	Title	Description
OG000	Napabucasin Plus FOLFIRI	All participants who were enrolled to Arm D to receive napabucasin administered orally, twice daily, in combination with FOLFIRI regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. This regimen was repeated every 14 days thereafter.

Units

Secondary

Progression Free Survival of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer

The effect of napabucasin given in combination with FOLFIRI on Progression Free Survival (PFS) of patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer. PFS of patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer.

Posted

Number

95% Confidence Interval

months

The time from the date of first treatment to the date of first documentation of disease progression or death due to any cause, up to thirty six months

ID	Title	Description
OG000	Napabucasin Plus FOLFIRI	Napabucasin administered orally, twice daily, in combination with FOLFIRI regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. This regimen was repeated every 14 days thereafter. Patients in this group had a baseline scan and at least one on study scan or died from any cause.

Units	Counts

Secondary

Overall Survival of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer

The effect of napabucasin given in combination with FOLFIRI on Overall Survival (OS) of patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer.

Analysis limited to a subset of group D in which patients had FOLFIRI/XELIRI refractory metastatic colorectal cancer.

Posted

Median

95% Confidence Interval

months

4 weeks after the patient has been off study treatment, every 3 months thereafter until death, the study closes, up to 36 months.

ID	Title	Description
OG000	Napabucasin Plus FOLFIRI	Napabucasin administered orally, twice daily, in combination with FOLFIRI regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. This regimen was repeated every 14 days thereafter . The patients in this subgroup were assessed to have FOLFIRI/XELIRI refractory metastatic colorectal cancer prior to enrollment.

Units	Counts
Participants

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	Napabucasin Plus FOLFOX6	All participants who received at least 1 dose of napabucasin administered orally, twice daily, in combination with FOLFOX6 regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously starting on Day 1 of Cycle 1, after the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous intravenous (IV) infusion.	104	115	52	115	115	115
EG001	Napabucasin Plus FOLFOX6 Plus Bevacizumab	All participants who received at least 1 dose of napabucasin administered orally, twice daily, in combination with FOLFOX6 plus bevacizumab regimen administered every 14 days. The regimen consisted of oxaliplatin 85 mg/m2 together with leucovorin 400 mg/m2 administered intravenously over 2 hours starting on Day1 of Cycle 1, following the first daily dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2 over 46-48 hours) by continuous IV infusion. Bevacizumab 5 mg/kg was administered intravenously following the oxaliplatin/leucovorin infusion.	31	41	10	41	41	41
EG002	Napabucasin Plus CAPOX	All participants who received at least 1 dose of napabucasin administered orally, twice daily, in combination with CAPOX regimen. The CAPOX regimen was administered orally (capecitabine) and by IV (oxaliplatin). Starting on Day 1 of Cycle 1, capecitabine 850 mg/m2 was administered orally BID following the first daily dose of napabucasin for 14 consecutive days and repeated every 21 days. Oxaliplatin 130 mg/m2 was administered intravenously over 2 hours, following the first daily dose of napabucasin starting on Day 1 of Cycle 1 and repeated every 21 days thereafter. If capecitabine was tolerated at the 850 mg/m2 BID dose, the dosage could have been increased to 1000 mg/m2 BID as tolerated after the first cycle.	82	87	40	87	87	87
EG003	Napabucasin Plus FOLFIRI	All participants who received at least 1 dose of napabucasin administered orally, twice daily, in combination with FOLFIRI regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. This regimen was repeated every 14 days thereafter.	129	156	58	156	156	156
EG004	Napabucasin Plus FOLFIRI Plus Bevacizumab	All participants who received at least 1 dose of napabucasin administered orally, twice daily, in combination with FOLFIRI plus bevacizumab regimen. Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 was administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. A 5-FU 400 mg/m2 bolus was administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5 FU 1200 mg/m2/day (total 2400 mg/m2) by continuous infusion. Bevacizumab 5 mg/kg was administered intravenously following the irinotecan/leucovorin infusion. This regimen was repeated every 14 days thereafter.	33	40	16	40	40	40
EG005	Napabucasin Plus Regorafenib	All participants who received at least 1 dose of napabucasin administered orally, twice daily, in combination with regorafenib 120 mg, administered orally once daily with a low-fat meal, starting on Day 1 of Cycle 1 for 21 consecutive days of every 28 days thereafter. If regorafenib was tolerated in the first cycle, the dosage could have been increased to 160 mg once daily as tolerated after the first cycle.	50	54	23	54	54	54
EG006	Napabucasin Plus Irinotecan	All participants who received at least 1 dose of napabucasin administered orally, twice daily, in combination with irinotecan 180 mg/m2, administered intravenously starting on Day 1 of Cycle 1, following the first dose of napabucasin. This regimen was repeated every 14 days thereafter.	2	2	2	2	2	2

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0005 affected115 at risk EG0012 affected41 at risk EG0025 affected87 at risk EG0030 affected156 at risk EG0042 affected40 at risk EG0051 affected54 at risk EG0060 affected2 at risk
Nausea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0025 affected87 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0005 affected115 at risk EG0010 affected41 at risk EG0029 affected87 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0004 affected115 at risk EG0010 affected41 at risk EG0023 affected87 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Ascites	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Dysphagia	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Haematemesis	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Colitis	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0011 affected41 at risk EG0021 affected87 at risk EG003
Enterocutaneous fistula	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Large intestine perforation	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Oesophagitis	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Small intestinal obstruction	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0013 affected41 at risk EG0021 affected87 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0011 affected41 at risk EG0020 affected87 at risk EG003
Enteritis	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0011 affected41 at risk EG0020 affected87 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Obstruction gastric	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Large instestinal obstruction	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Megacolon	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Pancreatitis	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Rectal haemorrhage	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Intestinal obstruction	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Pyrexia	General disorders	MedDRA 18.0	Systematic Assessment	EG0004 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Disease progression	General disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0025 affected87 at risk EG003
Chest pain	General disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Death	General disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Non-cardiac chest pain	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0011 affected41 at risk EG0020 affected87 at risk EG003
Oedema peripheral	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Pain	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Asthenia	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Chest discomfort	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Fatigue	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Mucosal inflammation	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Multi-organ failure	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Peripheral swelling	General disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Haemorrhage intranial	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Ischaemic cerebral infarction	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
somnolence	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
syncope	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
cerebrovascular accident	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
migraine	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
encephalopathy	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
headache	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
aphasia	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
hemiparesis	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
spinal cord compression	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0011 affected41 at risk EG0027 affected87 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0022 affected87 at risk EG003
Failure to thrive	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Neutrophil count decreased	Investigations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Weight decreased	Investigations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Blood bilirubin increased	Investigations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Blood creatinine increased	Investigations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Liver function test abnormal	Investigations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Lymphopenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Pathological fracture	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0022 affected87 at risk EG003
Nephrolithiasis	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0004 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0004 affected115 at risk EG0012 affected41 at risk EG0022 affected87 at risk EG003
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0011 affected41 at risk EG0020 affected87 at risk EG003
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Sepsis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0010 affected41 at risk EG0025 affected87 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0003 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Pneumonia	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Clostridium difficile colitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0011 affected41 at risk EG0020 affected87 at risk EG003
Influenza	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Lung abscess	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Perirectal abscess	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Salmonella sepsis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Septic shock	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Streptococcal bacteraemia	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Bacteraemia	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Device related infection	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Pyuria	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Urosepsis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Peritonitis bacterial	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Viral sepsis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
pelvic fracture	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
fall	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
hip fracture	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
subdural haematoma	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
stoma site haemorrhage	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
gastroenteritis radiation	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
overdose	Injury, poisoning and procedural complications	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Confusional state	Psychiatric disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0022 affected87 at risk EG003
Mental status changes	Psychiatric disorders	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
deep vein thrombosis	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0011 affected41 at risk EG0020 affected87 at risk EG003
embolism	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
haematoma	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
pelvic venous thrombosis	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
hypovolaemic shock	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
hypotension	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
hypertension	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 18.0	Systematic Assessment	EG0002 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
pancreatic carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
malignant pleural effusion	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
colon cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
metastases to central nervous system	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Cardiac arrest	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Cardiac failure congestive	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Myocardial infarction	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Angina pectoris	Cardiac disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Cholangitis	Hepatobiliary disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected115 at risk EG0010 affected41 at risk EG0022 affected87 at risk EG003
Bile duct obstruction	Hepatobiliary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0021 affected87 at risk EG003
Cholecystitis acute	Hepatobiliary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Hepatic function abnormal	Hepatobiliary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Cholecystitis	Hepatobiliary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Hepatic failure	Hepatobiliary disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003
Vision blurred	Eye disorders	MedDRA 18.0	Systematic Assessment	EG0000 affected115 at risk EG0010 affected41 at risk EG0020 affected87 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00094 affected115 at risk EG00137 affected41 at risk EG00275 affected87 at risk EG003139 affected156 at risk EG00439 affected40 at risk EG00542 affected54 at risk EG0061 affected2 at risk
Nausea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00087 affected115 at risk EG00132 affected41 at risk EG00263 affected87 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00066 affected115 at risk EG00125 affected41 at risk EG00249 affected87 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00061 affected115 at risk EG00122 affected41 at risk EG00237 affected87 at risk EG003
Stomatitis	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00012 affected115 at risk EG0015 affected41 at risk EG0022 affected87 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00027 affected115 at risk EG00111 affected41 at risk EG00218 affected87 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0013 affected41 at risk EG0027 affected87 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00010 affected115 at risk EG0012 affected41 at risk EG0029 affected87 at risk EG003
Ascites	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00011 affected115 at risk EG0013 affected41 at risk EG00211 affected87 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0007 affected115 at risk EG0016 affected41 at risk EG0022 affected87 at risk EG003
Flatulence	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0005 affected115 at risk EG0012 affected41 at risk EG0026 affected87 at risk EG003
Dysphagia	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00011 affected115 at risk EG0011 affected41 at risk EG0022 affected87 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0015 affected41 at risk EG0024 affected87 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0004 affected115 at risk EG0013 affected41 at risk EG0024 affected87 at risk EG003
Fatigue	General disorders	MedDRA 18.0	Systematic Assessment	EG00082 affected115 at risk EG00125 affected41 at risk EG00253 affected87 at risk EG003
Mucosal inflammation	General disorders	MedDRA 18.0	Systematic Assessment	EG00015 affected115 at risk EG0016 affected41 at risk EG0029 affected87 at risk EG003
Pyrexia	General disorders	MedDRA 18.0	Systematic Assessment	EG00019 affected115 at risk EG0016 affected41 at risk EG00213 affected87 at risk EG003
Oedema peripheral	General disorders	MedDRA 18.0	Systematic Assessment	EG00023 affected115 at risk EG0012 affected41 at risk EG00212 affected87 at risk EG003
Chills	General disorders	MedDRA 18.0	Systematic Assessment	EG0005 affected115 at risk EG0017 affected41 at risk EG0029 affected87 at risk EG003
Temperature intolerance	General disorders	MedDRA 18.0	Systematic Assessment	EG00015 affected115 at risk EG0014 affected41 at risk EG00215 affected87 at risk EG003
Asthenia	General disorders	MedDRA 18.0	Systematic Assessment	EG0009 affected115 at risk EG0013 affected41 at risk EG00211 affected87 at risk EG003
Neuropathy peripheral	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG00035 affected115 at risk EG00113 affected41 at risk EG00213 affected87 at risk EG003
Headache	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG00010 affected115 at risk EG0016 affected41 at risk EG0029 affected87 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG00015 affected115 at risk EG0015 affected41 at risk EG00213 affected87 at risk EG003
Peripheral sensory neuropathy	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG00019 affected115 at risk EG0019 affected41 at risk EG00214 affected87 at risk EG003
Dizziness	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG00013 affected115 at risk EG0015 affected41 at risk EG0027 affected87 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG00021 affected115 at risk EG00110 affected41 at risk EG00224 affected87 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG00024 affected115 at risk EG0018 affected41 at risk EG00219 affected87 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 18.0	Systematic Assessment	EG00012 affected115 at risk EG0012 affected41 at risk EG0025 affected87 at risk EG003
Neutrophil count decreased	Investigations	MedDRA 18.0	Systematic Assessment	EG00027 affected115 at risk EG0014 affected41 at risk EG0023 affected87 at risk EG003
Weight decreased	Investigations	MedDRA 18.0	Systematic Assessment	EG00025 affected115 at risk EG00110 affected41 at risk EG00217 affected87 at risk EG003
Urine ketone body present	Investigations	MedDRA 18.0	Systematic Assessment	EG0008 affected115 at risk EG0017 affected41 at risk EG0027 affected87 at risk EG003
Blood bilirubin increased	Investigations	MedDRA 18.0	Systematic Assessment	EG0007 affected115 at risk EG0014 affected41 at risk EG0026 affected87 at risk EG003
Platelet count decreased	Investigations	MedDRA 18.0	Systematic Assessment	EG00017 affected115 at risk EG0013 affected41 at risk EG0024 affected87 at risk EG003
Urine leukocyte esterase positive	Investigations	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0016 affected41 at risk EG0027 affected87 at risk EG003
White blood cell count decreased	Investigations	MedDRA 18.0	Systematic Assessment	EG00014 affected115 at risk EG0013 affected41 at risk EG0022 affected87 at risk EG003
Blood alkaline phosphatase increased	Investigations	MedDRA 18.0	Systematic Assessment	EG0008 affected115 at risk EG0015 affected41 at risk EG0025 affected87 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG00020 affected115 at risk EG00115 affected41 at risk EG0024 affected87 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG00029 affected115 at risk EG0019 affected41 at risk EG00215 affected87 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG00018 affected115 at risk EG0018 affected41 at risk EG00218 affected87 at risk EG003
Lymphopenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0007 affected115 at risk EG0015 affected41 at risk EG0024 affected87 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment	EG0007 affected115 at risk EG0015 affected41 at risk EG0024 affected87 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG00017 affected115 at risk EG0017 affected41 at risk EG0029 affected87 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0009 affected115 at risk EG0013 affected41 at risk EG0023 affected87 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0009 affected115 at risk EG0014 affected41 at risk EG0026 affected87 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0004 affected115 at risk EG0013 affected41 at risk EG0023 affected87 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 18.0	Systematic Assessment	EG0003 affected115 at risk EG0013 affected41 at risk EG0028 affected87 at risk EG003
Chromaturia	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG00015 affected115 at risk EG0013 affected41 at risk EG00210 affected87 at risk EG003
Proteinuria	Renal and urinary disorders	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0017 affected41 at risk EG0025 affected87 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0009 affected115 at risk EG0014 affected41 at risk EG0023 affected87 at risk EG003
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0011 affected41 at risk EG0029 affected87 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0012 affected41 at risk EG0024 affected87 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG00031 affected115 at risk EG0016 affected41 at risk EG00212 affected87 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG00019 affected115 at risk EG0018 affected41 at risk EG0026 affected87 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0008 affected115 at risk EG0014 affected41 at risk EG0023 affected87 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0004 affected115 at risk EG0017 affected41 at risk EG0021 affected87 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG00014 affected115 at risk EG0013 affected41 at risk EG0024 affected87 at risk EG003
Insomnia	Psychiatric disorders	MedDRA 18.0	Systematic Assessment	EG00010 affected115 at risk EG0015 affected41 at risk EG0025 affected87 at risk EG003
Anxiety	Psychiatric disorders	MedDRA 18.0	Systematic Assessment	EG00011 affected115 at risk EG0015 affected41 at risk EG0023 affected87 at risk EG003
Depression	Psychiatric disorders	MedDRA 18.0	Systematic Assessment	EG00013 affected115 at risk EG0013 affected41 at risk EG0025 affected87 at risk EG003
Hypertension	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0006 affected115 at risk EG0016 affected41 at risk EG0022 affected87 at risk EG003

ID	Term
D014498	Uracil
D011744	Pyrimidinones
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D056831	Coordination Complexes
D009930	Organic Chemicals
D005575	Formyltetrahydrofolates
D013763	Tetrahydrofolates
D005492	Folic Acid
D011622	Pterins
D011621	Pteridines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D003067	Coenzymes
D045762	Enzymes and Coenzymes
D002166	Camptothecin
D000470	Alkaloids
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins
D003841	Deoxycytidine
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D003853	Deoxyribonucleosides
D009705	Nucleosides
D009706	Nucleic Acids, Nucleotides, and Nucleosides

ID	Term
C000621033	napabucasin
D005472	Fluorouracil
D000077150	Oxaliplatin
D002955	Leucovorin
D000077146	Irinotecan
D000068258	Bevacizumab
D000069287	Capecitabine
C559147	regorafenib