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

• Sponsor: Sumitomo Pharma Oncology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02753127
• Collaborator: (none)
• Enrollment: 1,253
• Locations: 211
• Arms: 2
• Duration (Months): 59.3
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an international multi-center, prospective, open-label, randomized, adaptive design phase 3 trial of the cancer stem cell pathway inhibitor napabucasin plus standard bi-weekly FOLFIRI versus standard bi-weekly FOLFIRI in patients with previously treated metastatic colorectal cancer (CRC).

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: Napabucasin; Drug: Fluorouracil; Drug: Leucovorin; Drug: Irinotecan; Drug: Bevacizumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1253 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study of BBI-608 in Combination With 5-Fluorouracil, Leucovorin, Irinotecan (FOLFIRI) in Adult Patients With Previously Treated Metastatic Colorectal Cancer (CRC).
• Study Start Date: Jun 1, 2016
• Actual Primary Completion Date: Apr 28, 2020
• Actual Study Completion Date: May 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Napabucasin plus FOLFIRI 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.	Drug: Napabucasin; Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose).; Other Names: BBI-608 BBI608 BB608 ; Drug: Fluorouracil; Other Names: 5-FU Carac Efudex Fluoroplex Adrucil ; Drug: Leucovorin; Other Names: Folinic Acid ; Drug: Irinotecan; Other Names: Camptosar ; Drug: Bevacizumab; Other Names: Avastin
Active Comparator: FOLFIRI 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.	Drug: Fluorouracil; Other Names: 5-FU Carac Efudex Fluoroplex Adrucil ; Drug: Leucovorin; Other Names: Folinic Acid ; Drug: Irinotecan; Other Names: Camptosar ; Drug: Bevacizumab; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [Randomization to Date of Death from any cause or database cutoff date (28 Apr 2020) (Approximately 43 months)]

   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.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [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)]

   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.

2. Disease Control Rate (DCR) [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)]

   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

3. Objective Response Rate (ORR) [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)]

   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.

4. Mean Change From Baseline for Global Health Status at Time 2 (Cycle 5 Day 1) and Time 4 (Cycle 9 Day 1). [From baseline at Time 2 (Cycle 5 Day 1), approximately 57 days and Time 4 (Cycle 9 Day 1), approximately 113 days]

   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.

5. Mean Change From Baseline for Physical Functioning Status at Time 2 (Cycle 5 Day 1) and Time 4 (Cycle 9 Day 1). [From baseline at Time 2 (Cycle 5 Day 1) and Time 4 (Cycle 9 Day 1)]

   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.

6. Number of Patients With Adverse Events in the General Population [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 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written, signed consent for trial participation must be obtained from the patient appropriately in accordance with applicable ICH guidelines and local and regulatory requirements prior to the performance of any study specific procedure.

2. Must have histologically confirmed advanced CRC that is metastatic.

3. Must have failed treatment with one regimen containing a fluoropyrimidine, oxaliplatin with or without bevacizumab for metastatic disease. All patients must have received a minimum of 6 weeks of the first-line regimen that included bevacizumab (if applicable), oxaliplatin and a fluoropyrimidine in the same cycle. Treatment failure is defined as radiologic progression during or < 6 months after the last dose of first-line therapy.

4. FOLFIRI therapy is appropriate for the patient and is recommended by the Investigator.

5. Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as necessary to document all sites of disease performed within 21 days prior to randomization. Patients with either measurable disease or non-measurable evaluable disease are eligible.

6. Must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

7. Must be ≥ 18 years of age.

8. For male or female patient of child bearing potential: Must agree to use contraception or take measures to avoid pregnancy during the study and for 180 days for female and male patients, of the final FOLFIRI dose. Patients who receive single agent napabucasin without FOLFIRI must agree to use contraception or take measures to avoid pregnancy during the study and for 30 days for female patients and 90 days for male patients, of the final napabucasin dose.

9. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 5 days prior to randomization. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG.

10. Must have alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal (ULN) [≤ 5 × ULN in presence of liver metastases] within 14 days prior to randomization.

11. Must have hemoglobin (Hgb) ≥ 9.0 g/dL within 14 days prior to randomization. Must not have required transfusion of red blood cells within 1 week of baseline Hgb assessment.

12. Must have total bilirubin ≤ 1.5 × institutional ULN [≤ 2.0 x ULN in presence of liver metastases] within 14 days prior to randomization.

13. Must have creatinine ≤ 1.5 × institutional ULN or Creatinine Clearance > 50 ml/min (as calculated by the Cockcroft-Gault equation (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) within 14 days prior to randomization.

14. Must have absolute neutrophil count ≥ 1.5 x 10^9/L within 14 days prior to randomization.

15. Must have platelet count ≥ 100 x 10^9/L within 14 days prior to randomization. Must not have required transfusion of platelets within 1 week of baseline platelet assessment.

16. Patient must have adequate nutritional status with Body Mass Index (BMI) > 18 kg/m^2 and body weight of > 40 kg with serum albumin > 3 g/dL.

17. Other baseline laboratory evaluations, listed in Section 6.0, must be done within 14 days prior to randomization.

18. Patient must consent to provision of, and Investigator(s) must confirm access to and agree to submit a representative formalin fixed paraffin block of tumor tissue in order that the specific biomarker assays may be conducted. Submission of the tissue is to occur prior to randomization, unless approved by the Sponsor. Where local center regulations prohibit submission of blocks of tumor tissue, two 2 mm cores of tumor from the block and 10-30 unstained slides of whole sections of representative tumor tissue are preferred. Where two 2 mm cores of tumor from the block are unavailable, 10-30 unstained slides of whole sections of representative tumor tissue alone are acceptable. Where no previously resected or biopsied tumor tissue exists or is available, on the approval of the Sponsor/designated CRO, the patient may still be considered eligible for the study.

19. Patient must consent to provision of a sample of blood in order that the specific correlative marker assays may be conducted.

20. Patients must be accessible for treatment and follow-up. Patients registered on this trial must receive protocol treatment and be followed at the participating center. This implies there must be reasonable geographical limits placed on patients being considered for this trial. Investigators must ensure that the patients randomized on this trial will be available for complete documentation of the treatment, response assessment, adverse events, and follow-up.

21. Protocol treatment is to begin within 2 calendar days of patient randomization.

22. The patient is not receiving therapy in a concurrent clinical study and the patient agrees not to participate in other interventional clinical studies during their participation in this trial while on study treatment. Patients participating in surveys or observational studies are eligible to participate in this study.

Exclusion Criteria:

1. Anti-cancer chemotherapy or biologic therapy if administered prior to the first planned dose of study medication (napabucasin or FOLFIRI) within period of time equivalent to the usual cycle length of the regimen. An exception is made for oral fluoropyrimidines (e.g. capecitabine, S-1), where a minimum of 10 days since last dose must be observed prior to the first planned dose of study medication. Standard dose of bevacizumab (5 mg/kg) may be administered prior to FOLFIRI infusion, per Investigator decision, for as long as permanent decision to include or exclude bevacizumab is made prior to patient randomization. Radiotherapy, immunotherapy (including immunotherapy administered for non-malignant diseaseneoplastic treatment purposes), or investigational agents within four weeks of first planned dose of study medication, with the exception of a single dose of radiation up to 8 Gy (equal to 800 RAD) with palliative intent for pain control up to 14 days before randomization.

2. More than one prior chemotherapy regimen administered in the metastatic setting.

3. Major surgery within 4 weeks prior to randomization.

4. Patients with any known brain or leptomeningeal metastases are excluded, even if treated.

5. Women who are pregnant or breastfeeding. Women should not breastfeed while taking study treatment and for 4 weeks after the last dose of napabucasin or while undergoing treatment with FOLFIRI and for 180 days after the last dose of FOLFIRI.

6. Gastrointestinal disorder(s) which, in the opinion of the Qualified/Principal Investigator, would significantly impede the absorption of an oral agent (e.g. intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection).

7. Unable or unwilling to swallow napabucasin capsules daily.

8. Prior treatment with napabucasin.

9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.

10. Known hypersensitivity to 5-fluorouracil/leucovorin

11. Known dihydropyrimidine dehydrogenase (DPD) deficiency

12. Known hypersensitivity to irinotecan

13. Chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis)

14. Patients receiving treatment with St. John's wort or Phenytoin.

15. Patients who plan to receive yellow fever vaccine during the course of the study treatment.

16. Abnormal glucuronidation of bilirubin, known Gilbert's syndrome

17. Patients with QTc interval > 470 milliseconds

18. For patients to be treated with a regimen containing bevacizumab:

• History of cardiac disease: congestive heart failure (CHF) > New York Heart Association (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 (angina symptoms at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).

• Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management) as well as prior history of hypertensive crisis or hypertensive encephalopathy.

• History of arterial thrombotic or embolic events (within 6 months prior to study entry)

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease)

• Evidence of bleeding diathesis or clinically significant coagulopathy

• Major surgical procedure (including open biopsy, significant traumatic injury, etc.) within 28 days, or anticipation of the need for major surgical procedure during the course of the study as well as minor surgical procedure (excluding placement of a vascular access device or bone marrow biopsy) within 7 days prior to study enrollment

• Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).

• History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months

• Ongoing serious, non-healing wound, ulcer, or bone fracture

• Known hypersensitivity to any component of bevacizumab

• History of reversible posterior leukoencephalopathy syndrome (RPLS)

• History of hypersensitivity to Chinese hamster ovary (CHO) cells or other human or humanized recombinant antibodies.

1. Patients with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for > 3 years.

2. Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.

3. Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Oncology	Birmingham	Alabama	United States	35223
2	Mayo Clinic Arizona	Phoenix	Arizona	United States	85054
3	Arizona Oncology Associates, PC - HOPE	Tucson	Arizona	United States	85771
4	Comprehensive Blood and Cancer Center	Bakersfield	California	United States	93309
5	City of Hope- Comprehensive Care Center	Duarte	California	United States	91010
6	University of California-San Diego/Moores UCSD Cancer Center	La Jolla	California	United States	92093
7	Los Angeles Hematology Oncology Medical Group	Los Angeles	California	United States	90017
8	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
9	UCLA Hematology Oncology Santa Monica	Santa Monica	California	United States	90404
10	St. Joseph Heritage Healthcare	Santa Rosa	California	United States	95405
11	Rocky Mountain Cancer Centers	Denver	Colorado	United States	80218
12	St Mary's Hospital & Regional Med Center	Grand Junction	Colorado	United States	81501
13	Medical Oncology Hematology Consultants, PA	Newark	Delaware	United States	19713
14	Florida Cancer Specialists & Research Institute Fort Myers	Fort Myers	Florida	United States	33901
15	Memorial Cancer Institute at Memorial Hospital	Hollywood	Florida	United States	33021
16	Baptist Health Medical Group Oncology, LLC	Miami	Florida	United States	33176
17	Sarah Cannon Research Institution	Saint Petersburg	Florida	United States	33705
18	Palm Beach Cancer Institute	West Palm Beach	Florida	United States	33401
19	Piedmont Cancer Institute, PC	Atlanta	Georgia	United States	30318
20	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322
21	Suburban Hematology-Oncology Associates, PC - Lawrenceville	Lawrenceville	Georgia	United States	30046
22	Illinois Cancer Specialists	Arlington Heights	Illinois	United States	60005
23	Northshore University Healthsystem	Evanston	Illinois	United States	60201
24	Healthcare Research Network III, LLC	Tinley Park	Illinois	United States	60487
25	Northwestern Medicine Cancer Center	Warrenville	Illinois	United States	60555
26	Parkview Research Center	Fort Wayne	Indiana	United States	46845
27	Indiana University Health Goshen Center for Cancer Care	Goshen	Indiana	United States	46526
28	Michiana Hematology Oncology, PC	Mishawaka	Indiana	United States	46545
29	Cancer Center of Kansas	Wichita	Kansas	United States	67214
30	Dana Farber	Boston	Massachusetts	United States	02215
31	Umass Memorial Medical Center	Worcester	Massachusetts	United States	01655
32	University of Michigan Cancer Center	Ann Arbor	Michigan	United States
33	Minnesota Oncology Hematology, P.A.	Minneapolis	Minnesota	United States	55404
34	Mayo Clinic Arizona	Rochester	Minnesota	United States	55905
35	Research Medical Center	Kansas City	Missouri	United States	64132
36	Missouri Baptist Medical Center ACCRU Network Site	Saint Louis	Missouri	United States	63131
37	Saint Francis Cancer Treatment Center	Grand Island	Nebraska	United States	68803
38	Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
39	Cancer Research Network of Nebraska / Oncology Associates PC	Omaha	Nebraska	United States	68118
40	Tennessee Oncology PLLC	Omaha	Nebraska	United States	68118
41	Darthmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
42	Carol G. Simon Cancer Center	Morristown	New Jersey	United States	07962
43	University of New Mexico	Albuquerque	New Mexico	United States	87131
44	Montefiore Medical Center	Bronx	New York	United States	10467
45	Roswell Park Cancer Center	Buffalo	New York	United States	14263
46	North Shore Hematology Oncology Associates	East Setauket	New York	United States	11733
47	Weill Cornell Medical College	New York	New York	United States	10065
48	Southeastern Medical Oncology Center	Goldsboro	North Carolina	United States	27534
49	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
50	Toledo Clinic Cancer Centers	Toledo	Ohio	United States	43623
51	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
52	VA Pittsburgh Healthcare System	Pittsburgh	Pennsylvania	United States	15240
53	Medical University of South Carolina	Charleston	South Carolina	United States	29412
54	Sanford Cancer Center	Sioux Falls	South Dakota	United States	57104
55	University of Tennessee Medical Center	Knoxville	Tennessee	United States	37920
56	West Cancer Center	Memphis	Tennessee	United States	38138
57	The Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
58	Texas Oncology-Austin Midtown	Austin	Texas	United States	75705
59	Texas Oncology - Dallas Center	Dallas	Texas	United States	75203
60	Texas Oncology - Denton South	Denton	Texas	United States	76210
61	Texas Oncology - Fort Worth	Fort Worth	Texas	United States	76104
62	Millenium Oncology	Houston	Texas	United States	77090
63	Texas Health Physicians Group	Plano	Texas	United States	75093
64	Texas Oncology-San Antonio	San Antonio	Texas	United States	78217
65	Texas Oncology - Tyler	Tyler	Texas	United States	75702
66	Texas Oncology - Wichita Falls Texoma Cancer Center	Wichita Falls	Texas	United States	76310
67	Northern Utah Associates	Ogden	Utah	United States	84403
68	US Oncology - Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	22031
69	Fort Belvoir Community Hospital	Fort Belvoir	Virginia	United States	22060
70	Virginia Oncology Associates	Hampton	Virginia	United States	23666
71	Blue Ridge Cancer Care	Roanoke	Virginia	United States	24014
72	Virginia Mason	Seattle	Washington	United States	98101
73	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109-1023
74	Northwest Cancer Specialists, P.C.	Vancouver	Washington	United States	98684
75	Bankstown-Lidcombe Hospital	Bankstown	New South Wales	Australia	2200
76	St Vincent's Hospital	Darlinghurst	New South Wales	Australia	2010
77	St Vincent's hospital Melbourne	Fitzroy	New South Wales	Australia	3065
78	Port Macquaries Base Hospital	Port Macquarie	New South Wales	Australia	2444
79	Northern Cancer Institute	St Leonards	New South Wales	Australia	2065
80	Sunshine Coast Hospital and Health Service	Nambour	Queensland	Australia	4560
81	Gold Coast University Hosptial	Southport	Queensland	Australia	4215
82	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
83	The Queen Elizabeth Hospital	Woodville	South Australia	Australia	5011
84	Bendigo Hospital	Bendigo	Victoria	Australia	3550
85	Peninsula & South Eastern Haematology and Oncology Group	Frankston	Victoria	Australia	3199
86	Austin Hospital	Heidelberg	Victoria	Australia	3084
87	Western Health	Melbourne	Victoria	Australia	3021
88	Goulburn Valley Health	Shepparton	Victoria	Australia	3630
89	Prince of Wales Hospital	Randwick		Australia	2031
90	Imelda Ziekenhuis	Bonheiden	Antwerpen	Belgium	2820
91	Imelda Ziekenhuis	Bonheiden	Antwerpen	Belgium	2821
92	Imelda Ziekenhuis	Bonheiden	Antwerpen	Belgium	2822
93	AZ Turnhout - Campus Sint-Elisabeth	Turnhout	Antwerpen	Belgium	2300
94	Hôpital Erasme	Bruxelles	Brussels Capital Region	Belgium	1070
95	Grand Hôpital de Charleroi - Site Notre-Dame	Charleroi	Hainaut	Belgium	6000
96	CHU de Liège - Domaine Universitaire du Sart Tilman	Bruxelles	Liège	Belgium	1050
97	UZ Leuven - Campus Gasthuisberg	Leuven	Vlaams Brabant	Belgium	3000
98	AZ Sint-Jan Brugge - Oostende - Campus Sint-Jan	Brugge	West-Vlaanderen	Belgium	8000
99	AZ Sint-Lucas - Campus Sint-Lucas	Brugge	West-Vlaanderen	Belgium	8310
100	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
101	The Ottawa Hospital Cancer Centre	Ottawa	Ontario	Canada	K1H 8L6
102	University of Toronto - Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
103	Saint Michael's Hospital Li Ka Shing Knowledge Institute	Toronto	Ontario	Canada	M5B 1W8
104	St. Mary's Hospital Center	Montréal	Quebec	Canada	H3T 1M5
105	Hopital Notre-Dame du CHUM	Montréal	Quebec	Canada	HZL 4M1
106	Beijing Cancer Hospital	Beijing		China	100142
107	Henan Cancer Hospital	Henan		China	450008
108	Jiangsu Province Hospital	Jiangsu		China	210029
109	FN Hradec Kralove	Hradec Králové	Královéhradecký Kraj	Czechia	500 05
110	Fakultni nemocnice Brno	Brno		Czechia	625 00
111	Masarykuv onkologicky ustav	Brno		Czechia	656 53
112	Vseobecna fakultni nemocnice v Praze	Prague		Czechia	128 08
113	Centre Paul Papin	Angers		France	49055
114	Hospitalier Jean Minjoz	Besançon		France	25030
115	Hôpital Morvan - CHRU de Brest - cancérologie et d'hématolog	Brest		France	29609
116	CHU Estaing	Clermont Ferrand		France	63003
117	Centre de Lutte Contre le Cancer (CLCC)	Dijon		France	21079
118	CHU de Nantes - Hopital Hotel Dieu	Nantes		France	44093
119	Hôpital Européen Georges Pompidou - Digestive Oncology	Paris		France	75015
120	Hôpital Privé des Côtes d'Armor - Service oncologie	Plérin		France	22190
121	Hospital of Poitiers	Poitiers		France	86021
122	Centre Eugene Marquis	Rennes		France	35042
123	Centre Rene Gauducheau	Saint-Herblain		France	44805
124	Leopoldina Krankenhaus Med. Klinik 2	Schweinfurt	Bayern	Germany	97422
125	Schwerpunkpraxis für Hämatologie und Onkologie	Magdeburg	Sachsen-Anhalt	Germany	39104
126	Universitätsklinikum Carl Gustav Carus Dresden	Dresden	Sachsen	Germany	01307
127	Gesundheitszentrum Wetterau	Bad Nauheim		Germany	61231
128	Vivantes Klinikum Am Urban	Berlin		Germany	10967
129	Charite - Campus Benjamin Franklin (Cbf)	Berlin		Germany	12203
130	DRK Kliniken Berlin Koepenick	Berlin		Germany	12559
131	Charité Universitätsmedizin	Berlin		Germany	13353
132	MVZ Onkologischer Schwerpunkt am Oskar-Helene-Heim	Berlin		Germany	14195
133	Facharztzentrum Eppendorf	Hamburg		Germany	20249
134	Asklepios Klinik Altona	Hamburg		Germany	22763
135	Universitätsklinikum Marburg	Marburg		Germany	35033
136	Medizinische Universitaetsklin	Ulm		Germany	89081
137	Pamela Youde Nethersole Eastern Hospital	Hong Kong		Hong Kong	150001
138	Queen Mary Hospital	Hong Kong		Hong Kong
139	Ha'Emek Medical Center	Afula		Israel	1834111
140	The Barzilai Medical Center - Oncology Institute	Ashkelon		Israel	7830604
141	Soroka University Medical Center	Be'er Sheva		Israel	8410101
142	Shaare Zedek Medical center	Jerusalem		Israel	91031
143	Meir Medical Center	Kefar Saba		Israel	4428164
144	Rabin MC - Oncology, Davidoff Center	Petah tikva		Israel	49100
145	Ziv Medical Center (The Rebecca Sieff Hospital)	Safed		Israel	13100
146	The Chaim Sheba Medical Centre - Division of Oncology	Tel HaShomer		Israel	52621
147	Tel Aviv Sourasky Medical Center - Oncology	Tel-Aviv		Israel	6423906
148	AOU Ospedali Riuniti Umberto I - GM.Lanc	Torrette Di Ancona	Ancona	Italy	60126
149	Ospedale Santa Maria del Prato	Feltre	Belluno	Italy	32032
150	Irccs Irst	Meldola	Forli	Italy	47014
151	AUSL della Romagna, Osp. degli Infermi	Faenza	Ravenna	Italy	48018
152	Policlinico S.Orsola Malpighi, AOU di Bologna	Bologna		Italy	40138
153	PO di Cremona, ASST di Cremona	Cremona		Italy	26100
154	AO S. Martino, IRCCS, IST	Genova		Italy	16132
155	Ieo, Irccs	Milano		Italy	20141
156	AOU Policlinico di Modena	Modena		Italy	41124
157	Università degli studi della Campania "L.Vanvitelli"	Napoli		Italy	80131
158	Ospedale Guglielmo da Saliceto, AUSL Piacenza	Piacenza		Italy	29121
159	AOU Città della Salute e della Scienza di Torino - Molinette	Torino		Italy	10126
160	Aichi Cancer Center Hospital	Nagoya	Aichi	Japan	464-8681
161	National Cancer Center Hospital East	Kashiwa	Chiba	Japan	277-8577
162	National Hospital Organization Shikoku Cancer Center	Matsunami	Ehime	Japan	791-0280
163	Hokkaido University Hospital	Sapporo	Hokkaido	Japan	060-8648
164	Kobe City Medical Center General Hospital	Kobe	Hyogo	Japan	650-0047
165	ST. Marianna University School of Medicine	Kawasaki	Kanagawa	Japan	216-8511
166	Osaka University Hospital	Suita	Osaka	Japan	565-0871
167	Osaka Medical College Hospital	Takatsuki	Osaka	Japan	569-8686
168	Saitama Cancer Center	Kita-Adachi	Saitama	Japan	362-0806
169	Shizuoka Cancer Center	Sunto	Shizuoka	Japan	411-8777
170	Medical Hospital, Tokyo Medical and Dental University	Bunkyo-ku	Tokyo	Japan	113-8510
171	National Cancer Center Hospital	Chuo-ku	Tokyo	Japan	104-0045
172	The cancer insitute hospital of JFCR (Japanese Foundation For Cancer Research)	Koto-ku	Tokyo	Japan	135-8550
173	National Kyushu Cancer Center	Fukuoka		Japan	811-1395
174	Osaka Medical Center for Cancer and Cardiovascular Diseases	Osaka		Japan	537-8511
175	National Hospital Organization Osaka National Hospital	Osaka		Japan	540-0006
176	Yeungnam University Medical Center	Daegu	Daegu Gwang'yeogsi	Korea, Republic of	42415
177	National Cancer Centre	Goyang	Gyeonggido	Korea, Republic of	10408
178	Ajou University Hospital	Suwon	Gyeonggido	Korea, Republic of	16499
179	Gachon University Gil Medical Center	Incheon	Incheon Gwang'yeogsi	Korea, Republic of	21565
180	Korea University Anam Hospital	Seoul	Seoul Teugbyeolsi	Korea, Republic of	02841
181	Samsung Medical Center	Seoul	Seoul Teugbyeolsi	Korea, Republic of	06351
182	Korea University Guro Hospital	Seoul	Seoul Teugbyeolsi	Korea, Republic of	08308
183	Severance Hospital, Yonsei University Health System	Seoul	Seoul Teugbyeolsi	Korea, Republic of	120-752
184	Medisch Centrum Leeuwarden	Leeuwarden	Friesland	Netherlands	8934 AD
185	Academisch Medisch Centrum	Amsterdam		Netherlands	1055 AZ
186	Spaarne Gasthuis	Hoofddorp		Netherlands	2134 TM
187	Maastricht UMC	Maastricht		Netherlands	6229 HX
188	Elizabeth Tweesteden Ziekenhuis locatie Tilburg	Tilburg		Netherlands	5042 SB
189	National University Cancer Institute	Singapore	Central Singapore	Singapore	119228
190	National Cancer Centre	Singapore	Central Singapore	Singapore	169610
191	Raffles Hospital	Singapore	Central Singapore	Singapore	188770
192	Hospital General Universitario de Elche	Elche	Alicante	Spain	3203
193	H.U.V. del Rocío	Sevilla	Andalucía	Spain	41013
194	Hospital Universitario Central de Asturias	Oviedo	Asturias	Spain	33011
195	Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain	8916
196	Complexo Hospital Universitario A Coruña	A Coruña	Galicia	Spain	15006
197	Hospital Universitario Fundacion Alcorcon (HUFA)	Alcorcón	Madrid	Spain	28922
198	Hospital Universitario Puerta de Hierro-Majadahonda	Majadahonda	Madrid	Spain	28222
199	Consorci Hospital General Universitari Valencia (CHGUV)	Comunidad Valenciana	Valencia	Spain	46014
200	Hospital Son Llatzer	Baleares		Spain	7198
201	Hospital Universitario Vall d'Hebrón	Barcelona		Spain	080035
202	Hospital del Mar	Barcelona		Spain	08003
203	Hospital Clinic i Provincial de Barcelona	Barcelona		Spain	8036
204	Hospital Universitario Gregorio Marañón	Madrid		Spain	28016
205	Hospital Clínico San Carlos	Madrid		Spain	28040
206	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
207	Hospital Universitario La Paz	Madrid		Spain	28046
208	Hospital Universitario Virgen de la Arrixaca	Murcia		Spain	30120
209	Hospital Universitario Virgen de la Macarena	Sevilla		Spain	41009
210	H.C.U.Valencia	Valencia		Spain	46010
211	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009

Sponsors and Collaborators

• Sumitomo Pharma Oncology, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Oct 25, 2019
• Statistical Analysis Plan - Dec 15, 2020

More Information

Publications

None provided.

• Responsible Party: Sumitomo Pharma Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT02753127
• Other Study ID Numbers: CanStem303C; BB608-303CRC; 2016-001627-31
• First Posted: Apr 27, 2016
• Last Update Posted: Apr 26, 2022
• Last Verified: Mar 1, 2022

• Keywords provided by Sumitomo Pharma Oncology, Inc.: Colorectal Neoplasms; Colonic Diseases; Digestive System Diseases; Digestive System Neoplasms; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Intestinal Diseases; Intestinal Neoplasms; Neoplasms; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Rectal Diseases
• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Bevacizumab; Fluorouracil; Irinotecan

Study Results

Participant Flow

Recruitment Details	1253 participants were randomized between October 2016 and March 2019.
Pre-assignment Detail	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 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

Baseline Characteristics

Arm/Group Title	Napabucasin + FOLFIRI ± Bevacizumab	FOLFIRI ± Bevacizumab	Total
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 Participants	624	629	1253
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.1 (11.17)	59.6 (11.14)	59.8 (11.16)
Sex: Female, Male (Count of Participants)
Female	240 38.5%	254 40.4%	494 39.4%
Male	384 61.5%	375 59.6%	759 60.6%
Race/Ethnicity, Customized (participants) [Number]
White	375 60.1%	370 58.8%	745 59.5%
Black or African American	29 4.6%	38 6%	67 5.3%
Asian	197 31.6%	194 30.8%	391 31.2%
American Indian or Alaska Native	0 0%	1 0.2%	1 0.1%
Native Hawaiian or Other Pacific Islander	1 0.2%	0 0%	1 0.1%
Other	9 1.4%	12 1.9%	21 1.7%
Missing	13 2.1%	14 2.2%	27 2.2%
Region of Enrollment (participants) [Number]
Singapore	8 1.3%	9 1.4%	17 1.4%
Hong Kong	1 0.2%	11 1.7%	12 1%
United States	203 32.5%	209 33.2%	412 32.9%
Czechia	18 2.9%	19 3%	37 3%
Japan	63 10.1%	63 10%	126 10.1%
Spain	74 11.9%	62 9.9%	136 10.9%
Canada	21 3.4%	15 2.4%	36 2.9%
Netherlands	16 2.6%	21 3.3%	37 3%
South Korea	44 7.1%	39 6.2%	83 6.6%
Belgium	16 2.6%	24 3.8%	40 3.2%
China	62 9.9%	59 9.4%	121 9.7%
Italy	22 3.5%	29 4.6%	51 4.1%
Israel	8 1.3%	10 1.6%	18 1.4%
Australia	36 5.8%	24 3.8%	60 4.8%
France	20 3.2%	21 3.3%	41 3.3%
Germany	12 1.9%	14 2.2%	26 2.1%
ECOG Performance Status (Count of Participants)
ECOG: 0	333 53.4%	332 52.8%	665 53.1%
ECOG: 1	291 46.6%	297 47.2%	588 46.9%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
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 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
Measure Participants	624	629
Overall Survival (OS), General Population(GP)	14.29	13.83
Overall Survival (OS), ITT-pSTAT3(+)	13.17	12.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	General population
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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
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
	Parameter Dispersion	Type: Value:
	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 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. 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 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
Measure Participants	624	629
Progression-Free Survival (PFS), General Population(GP)	5.55	5.62
Progression-Free Survival (PFS) , ITT-pSTAT3(+)	5.39	5.55

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	General population
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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
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
	Parameter Dispersion	Type: Value:
	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 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 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.
Measure Participants	593	609
Disease Control Rate (DCR), General Population(GP)	69.6 11.2%	69.1 11%
Disease Control Rate (DCR), ITT-pSTAT3(+)	67.2 10.8%	70.3 11.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	General population
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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
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
	Parameter Dispersion	Type: Value:
	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 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 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.
Measure Participants	593	609
Objective Response Rate (ORR), General Population(GP)	13.8 2.2%	14.6 2.3%
Objective Response Rate (ORR), ITT-pSTAT3(+)	11.9 1.9%	13.9 2.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Napabucasin + FOLFIRI ± Bevacizumab, FOLFIRI ± Bevacizumab
	Comments	General population
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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
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
	Parameter Dispersion	Type: Value:
	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 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 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.
Measure Participants	622	626
Mean Change From Baseline for Global Health status at Time 2 (Cycle 5 Day 1). General Population	-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	-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 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 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.
Measure Participants	622	626
Mean Change From Baseline for Physical Functioning at Time 2 (Cycle 5 Day 1). General Population	-5.86 (17.204)	-3.94 (14.472)
Mean Change From Baseline for Physical Functioning at Time 4 (Cycle 9 Day 1). General Population	-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 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 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.
Measure Participants	622	610
Number of Patients with Adverse Events in the General Population	619 99.2%	602 95.7%
Number of Patients with Adverse Events in the pSTAT3(+) Subpopulation	275 44.1%	266 42.3%

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 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 (%)	# Events	Affected / at Risk (%)	# Events
Total	507/624 (81.3%)		499/629 (79.3%)
Serious Adverse Events
	Napabucasin + FOLFIRI ± Bevacizumab		FOLFIRI ± Bevacizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	234/622 (37.6%)		201/610 (33%)
Blood and lymphatic system disorders
Anaemia	9/622 (1.4%)		4/610 (0.7%)
Febrile Neutropenia	8/622 (1.3%)		12/610 (2%)
Neutropenia	4/622 (0.6%)		3/610 (0.5%)
Thrombocytopenia	3/622 (0.5%)		2/610 (0.3%)
Pancytopenia	2/622 (0.3%)		0/610 (0%)
Bone Marrow Failure	1/622 (0.2%)		1/610 (0.2%)
Disseminated Intravascular Coagulation	1/622 (0.2%)		0/610 (0%)
Leukopenia	1/622 (0.2%)		1/610 (0.2%)
Thrombocytosis	1/622 (0.2%)		0/610 (0%)
Cardiac disorders
Atrial Fibrillation	3/622 (0.5%)		4/610 (0.7%)
Acute Coronary Syndrome	1/622 (0.2%)		0/610 (0%)
Acute Myocardial Infarction	1/622 (0.2%)		1/610 (0.2%)
Atrial Flutter	1/622 (0.2%)		1/610 (0.2%)
Cardiac Arrest	1/622 (0.2%)		1/610 (0.2%)
Cardiac Failure	1/622 (0.2%)		0/610 (0%)
Tachycardia	1/622 (0.2%)		0/610 (0%)
Ventricular Fibrillation	1/622 (0.2%)		0/610 (0%)
Myocardial Infarction	0/622 (0%)		1/610 (0.2%)
Myocarditis	0/622 (0%)		1/610 (0.2%)
Gastrointestinal disorders
Diarrhoea	39/622 (6.3%)		19/610 (3.1%)
Abdominal Pain	17/622 (2.7%)		16/610 (2.6%)
Intestinal Obstruction	10/622 (1.6%)		15/610 (2.5%)
Small Intestinal Obstruction	10/622 (1.6%)		12/610 (2%)
Vomiting	10/622 (1.6%)		8/610 (1.3%)
Nausea	9/622 (1.4%)		4/610 (0.7%)
Ileus	4/622 (0.6%)		8/610 (1.3%)
Ascites	3/622 (0.5%)		3/610 (0.5%)
Intestinal Perforation	3/622 (0.5%)		2/610 (0.3%)
Large Intestinal Obstruction	3/622 (0.5%)		4/610 (0.7%)
Upper Gastrointestinal Haemorrhage	3/622 (0.5%)		1/610 (0.2%)
Colitis	2/622 (0.3%)		3/610 (0.5%)
Enterocolitis	2/622 (0.3%)		0/610 (0%)
Lower Gastrointestinal Haemorrhage	2/622 (0.3%)		1/610 (0.2%)
Oesophageal Varices Haemorrhage	2/622 (0.3%)		0/610 (0%)
Pancreatitis	2/622 (0.3%)		0/610 (0%)
Rectal Haemorrhage	2/622 (0.3%)		1/610 (0.2%)
Abdominal Hernia Obstructive	1/622 (0.2%)		0/610 (0%)
Diarrhoea Haemorrhagic	1/622 (0.2%)		0/610 (0%)
Duodenal Ulcer Haemorrhage	1/622 (0.2%)		0/610 (0%)
Enteritis	1/622 (0.2%)		0/610 (0%)
Gastrointestinal Disorder	1/622 (0.2%)		0/610 (0%)
Gastrointestinal Haemorrhage	1/622 (0.2%)		1/610 (0.2%)
Gastrointestinal Inflammation	1/622 (0.2%)		1/610 (0.2%)
Gastrointestinal Perforation	1/622 (0.2%)		0/610 (0%)
Gastrointestinal Toxicity	1/622 (0.2%)		0/610 (0%)
Haematochezia	1/622 (0.2%)		1/610 (0.2%)
Haemorrhoidal Haemorrhage	1/622 (0.2%)		0/610 (0%)
Haemorrhoids	1/622 (0.2%)		0/610 (0%)
Inguinal Hernia Strangulated	1/622 (0.2%)		0/610 (0%)
Large Intestinal Stenosis	1/622 (0.2%)		0/610 (0%)
Melaena	1/622 (0.2%)		0/610 (0%)
Obstruction Gastric	1/622 (0.2%)		1/610 (0.2%)
Pancreatitis Acute	1/622 (0.2%)		0/610 (0%)
Pneumoperitoneum	1/622 (0.2%)		0/610 (0%)
Proctalgia	1/622 (0.2%)		0/610 (0%)
Abdominal Distension	0/622 (0%)		1/610 (0.2%)
Colitis Ischaemic	0/622 (0%)		2/610 (0.3%)
Constipation	0/622 (0%)		1/610 (0.2%)
Duodenal Perforation	0/622 (0%)		1/610 (0.2%)
Gastric Ulcer Perforation	0/622 (0%)		1/610 (0.2%)
Inguinal Hernia	0/622 (0%)		1/610 (0.2%)
Large Intestine Perforation	0/622 (0%)		1/610 (0.2%)
Mouth Ulceration	0/622 (0%)		1/610 (0.2%)
Pneumatosis Intestinalis	0/622 (0%)		1/610 (0.2%)
Stomatitis	0/622 (0%)		2/610 (0.3%)
Subileus	0/622 (0%)		1/610 (0.2%)
Toothache	0/622 (0%)		1/610 (0.2%)
General disorders
Pyrexia	18/622 (2.9%)		16/610 (2.6%)
Disease Progression	17/622 (2.7%)		15/610 (2.5%)
General Physical Health Deterioration	5/622 (0.8%)		5/610 (0.8%)
Asthenia	4/622 (0.6%)		4/610 (0.7%)
Fatigue	4/622 (0.6%)		2/610 (0.3%)
Death	2/622 (0.3%)		1/610 (0.2%)
Mucosal Inflammation	2/622 (0.3%)		1/610 (0.2%)
Non-Cardiac Chest Pain	2/622 (0.3%)		1/610 (0.2%)
Chills	1/622 (0.2%)		0/610 (0%)
Malaise	1/622 (0.2%)		1/610 (0.2%)
Mucosal Toxicity	1/622 (0.2%)		0/610 (0%)
Oedema Peripheral	1/622 (0.2%)		2/610 (0.3%)
Pain	1/622 (0.2%)		0/610 (0%)
Inflammation	0/622 (0%)		1/610 (0.2%)
Hepatobiliary disorders
Hyperbilirubinaemia	3/622 (0.5%)		1/610 (0.2%)
Bile Duct Obstruction	2/622 (0.3%)		1/610 (0.2%)
Cholangitis	2/622 (0.3%)		0/610 (0%)
Cholecystitis Acute	2/622 (0.3%)		1/610 (0.2%)
Cholecystitis	1/622 (0.2%)		1/610 (0.2%)
Gallbladder Necrosis	1/622 (0.2%)		0/610 (0%)
Hepatic Function Abnormal	1/622 (0.2%)		0/610 (0%)
Jaundice Cholestatic	1/622 (0.2%)		1/610 (0.2%)
Bile Duct Stenosis	0/622 (0%)		1/610 (0.2%)
Cholelithiasis	0/622 (0%)		1/610 (0.2%)
Liver Injury	0/622 (0%)		1/610 (0.2%)
Immune system disorders
Drug Hypersensitivity	1/622 (0.2%)		0/610 (0%)
Anaphylactic Reaction	0/622 (0%)		2/610 (0.3%)
Infections and infestations
Sepsis	7/622 (1.1%)		10/610 (1.6%)
Urinary Tract Infection	6/622 (1%)		0/610 (0%)
Pneumonia	4/622 (0.6%)		8/610 (1.3%)
Anal Abscess	2/622 (0.3%)		0/610 (0%)
Bacteraemia	2/622 (0.3%)		2/610 (0.3%)
Clostridium Difficile Colitis	2/622 (0.3%)		1/610 (0.2%)
Infection	2/622 (0.3%)		1/610 (0.2%)
Abdominal Infection	1/622 (0.2%)		0/610 (0%)
Abdominal Sepsis	1/622 (0.2%)		0/610 (0%)
Appendicitis Perforated	1/622 (0.2%)		0/610 (0%)
Bacterial Sepsis	1/622 (0.2%)		0/610 (0%)
Cellulitis	1/622 (0.2%)		0/610 (0%)
Clostridium Difficile Infection	1/622 (0.2%)		0/610 (0%)
Colonic Abscess	1/622 (0.2%)		0/610 (0%)
Device Related Infection	1/622 (0.2%)		1/610 (0.2%)
Diverticulitis	1/622 (0.2%)		0/610 (0%)
Empyema	1/622 (0.2%)		0/610 (0%)
Enterocolitis Infectious	1/622 (0.2%)		0/610 (0%)
Herpes Zoster	1/622 (0.2%)		0/610 (0%)
Infected Dermal Cyst	1/622 (0.2%)		0/610 (0%)
Lung Infection	1/622 (0.2%)		0/610 (0%)
Nosocomial Infection	1/622 (0.2%)		0/610 (0%)
Perirectal Abscess	1/622 (0.2%)		0/610 (0%)
Peritonitis	1/622 (0.2%)		1/610 (0.2%)
Peritonsillar Abscess	1/622 (0.2%)		0/610 (0%)
Pneumonia Influenzal	1/622 (0.2%)		0/610 (0%)
Pseudomonas Bronchitis	1/622 (0.2%)		0/610 (0%)
Rectal Abscess	1/622 (0.2%)		0/610 (0%)
Retroperitoneal Abscess	1/622 (0.2%)		0/610 (0%)
Septic Shock	1/622 (0.2%)		4/610 (0.7%)
Urinary Tract Infection	1/622 (0.2%)		0/610 (0%)
Urosepsis	1/622 (0.2%)		1/610 (0.2%)
Viral Infection	1/622 (0.2%)		0/610 (0%)
Abdominal Abscess	0/622 (0%)		1/610 (0.2%)
Abdominal Wall Abscess	0/622 (0%)		1/610 (0.2%)
Abscess Jaw	0/622 (0%)		1/610 (0.2%)
Abscess Rupture	0/622 (0%)		1/610 (0.2%)
Anorectal Infection	0/622 (0%)		1/610 (0.2%)
Bronchitis	0/622 (0%)		1/610 (0.2%)
Coccidioidomycosis	0/622 (0%)		1/610 (0.2%)
Community Acquired	0/622 (0%)		1/610 (0.2%)
Cystitis	0/622 (0%)		1/610 (0.2%)
Endocarditis	0/622 (0%)		1/610 (0.2%)
Epididymitis	0/622 (0%)		1/610 (0.2%)
Fungal Sepsis	0/622 (0%)		1/610 (0.2%)
Lower Respiratory Tract Infection	0/622 (0%)		1/610 (0.2%)
Necrotising Fasciitis	0/622 (0%)		1/610 (0.2%)
Ophthalmic Herpes Zoster	0/622 (0%)		1/610 (0.2%)
Pelvic Abscess	0/622 (0%)		1/610 (0.2%)
Pelvic Infection	0/622 (0%)		1/610 (0.2%)
Pharyngitis	0/622 (0%)		1/610 (0.2%)
Pneumonia Pneumococcal	0/622 (0%)		1/610 (0.2%)
Psoas Abscess	0/622 (0%)		1/610 (0.2%)
Pulmonary Sepsis	0/622 (0%)		1/610 (0.2%)
Pyelonephritis	0/622 (0%)		4/610 (0.7%)
Pyonephrosis	0/622 (0%)		1/610 (0.2%)
Respiratory Tract	0/622 (0%)		1/610 (0.2%)
Streptococcal Bacteraemia	0/622 (0%)		1/610 (0.2%)
Injury, poisoning and procedural complications
Accidental Overdose	2/622 (0.3%)		0/610 (0%)
Ankle Fracture	2/622 (0.3%)		0/610 (0%)
Hip Fracture	2/622 (0.3%)		1/610 (0.2%)
Infusion Related Reaction	2/622 (0.3%)		0/610 (0%)
Spinal Fracture	2/622 (0.3%)		0/610 (0%)
Stoma Site Haemorrhage	2/622 (0.3%)		3/610 (0.5%)
Femoral Neck Fracture	1/622 (0.2%)		0/610 (0%)
Femur Fracture	1/622 (0.2%)		0/610 (0%)
Gastrointestinal Stoma Complication	1/622 (0.2%)		1/610 (0.2%)
Lumbar Vertebral Fracture	1/622 (0.2%)		1/610 (0.2%)
Road Traffic Accident	1/622 (0.2%)		0/610 (0%)
Stoma Complication	1/622 (0.2%)		0/610 (0%)
Overdose	0/622 (0%)		1/610 (0.2%)
Subdural Haematoma	0/622 (0%)		1/610 (0.2%)
Investigations
Blood Bilirubin Increased	2/622 (0.3%)		1/610 (0.2%)
Neutrophil Count Decreased	2/622 (0.3%)		8/610 (1.3%)
Platelet Count Decreased	2/622 (0.3%)		1/610 (0.2%)
Alanine Aminotransferase Increased	1/622 (0.2%)		0/610 (0%)
Aspartate Aminotransferase Increased	1/622 (0.2%)		0/610 (0%)
Myocardial Necrosis Marker Increased	1/622 (0.2%)		0/610 (0%)
Red Blood Cell Count Decreased	1/622 (0.2%)		0/610 (0%)
Blood Uric Acid Increased	0/622 (0%)		1/610 (0.2%)
White Blood Cell Count Decreased	0/622 (0%)		2/610 (0.3%)
Metabolism and nutrition disorders
Dehydration	15/622 (2.4%)		9/610 (1.5%)
Hypokalaemia	5/622 (0.8%)		6/610 (1%)
Decreased Appetite	4/622 (0.6%)		3/610 (0.5%)
Failure To Thrive	1/622 (0.2%)		1/610 (0.2%)
Hyperglycaemia	1/622 (0.2%)		0/610 (0%)
Hyperkalaemia	1/622 (0.2%)		0/610 (0%)
Hypoglycaemia	1/622 (0.2%)		0/610 (0%)
Hyponatraemia	1/622 (0.2%)		0/610 (0%)
Hypovolaemia	1/622 (0.2%)		0/610 (0%)
Hypophagia	0/622 (0%)		1/610 (0.2%)
Musculoskeletal and connective tissue disorders
Back Pain	3/622 (0.5%)		4/610 (0.7%)
Muscular Weakness	1/622 (0.2%)		0/610 (0%)
Myopathy	1/622 (0.2%)		0/610 (0%)
Pain In Extremity	1/622 (0.2%)		0/610 (0%)
Fracture Pain	0/622 (0%)		1/610 (0.2%)
Osteonecrosis Of Jaw	0/622 (0%)		1/610 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant Ascites	1/622 (0.2%)		0/610 (0%)
Metastases To Kidney	1/622 (0.2%)		0/610 (0%)
Metastases To Liver	1/622 (0.2%)		0/610 (0%)
Metastases To Lung	1/622 (0.2%)		0/610 (0%)
Pituitary Tumour Benign	1/622 (0.2%)		0/610 (0%)
Tumour Haemorrhage	1/622 (0.2%)		0/610 (0%)
Colon Cancer Metastatic	0/622 (0%)		1/610 (0.2%)
Metastases To Heart	0/622 (0%)		1/610 (0.2%)
Metastases To Peritoneum	0/622 (0%)		1/610 (0.2%)
Tumour Pain	0/622 (0%)		1/610 (0.2%)
Nervous system disorders
Syncope	2/622 (0.3%)		3/610 (0.5%)
Altered State Of Consciousness	1/622 (0.2%)		0/610 (0%)
Cerebral Infarction	1/622 (0.2%)		0/610 (0%)
Presyncope	1/622 (0.2%)		0/610 (0%)
Subarachnoid Haemorrhage	1/622 (0.2%)		0/610 (0%)
Superior Sagittal Sinus Thrombosis	1/622 (0.2%)		0/610 (0%)
Transient Ischaemic Attack	1/622 (0.2%)		0/610 (0%)
Encephalopathy	0/622 (0%)		1/610 (0.2%)
Seizure	0/622 (0%)		1/610 (0.2%)
Spinal Cord Compression	0/622 (0%)		1/610 (0.2%)
Spinal Cord Disorder	0/622 (0%)		1/610 (0.2%)
Product Issues
Device Dislocation	1/622 (0.2%)		0/610 (0%)
Thrombosis In Device	1/622 (0.2%)		0/610 (0%)
Psychiatric disorders
Confusional State	1/622 (0.2%)		0/610 (0%)
Hallucination	1/622 (0.2%)		0/610 (0%)
Mental Status Changes	1/622 (0.2%)		0/610 (0%)
Aggression	0/622 (0%)		1/610 (0.2%)
Anxiety	0/622 (0%)		1/610 (0.2%)
Renal and urinary disorders
Acute Kidney Injury	7/622 (1.1%)		3/610 (0.5%)
Acute Prerenal Failure	1/622 (0.2%)		0/610 (0%)
Haematuria	1/622 (0.2%)		1/610 (0.2%)
Prerenal Failure	1/622 (0.2%)		0/610 (0%)
Renal Impairment	1/622 (0.2%)		0/610 (0%)
Ureterolithiasis	1/622 (0.2%)		1/610 (0.2%)
Hydronephrosis	0/622 (0%)		2/610 (0.3%)
Hydroureter	0/622 (0%)		1/610 (0.2%)
Urinary Retention	0/622 (0%)		2/610 (0.3%)
Urinary Tract Obstruction	0/622 (0%)		2/610 (0.3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	12/622 (1.9%)		9/610 (1.5%)
Pleural Effusion	5/622 (0.8%)		2/610 (0.3%)
Dyspnoea	3/622 (0.5%)		1/610 (0.2%)
Pneumonitis	2/622 (0.3%)		0/610 (0%)
Respiratory Failure	2/622 (0.3%)		2/610 (0.3%)
Aspiration	1/622 (0.2%)		0/610 (0%)
Chronic Obstructive Pulmonary Disease	1/622 (0.2%)		0/610 (0%)
Interstitial Lung Disease	1/622 (0.2%)		1/610 (0.2%)
Lung Infiltration	1/622 (0.2%)		0/610 (0%)
Pneumothorax	1/622 (0.2%)		0/610 (0%)
Pulmonary Artery Thrombosis	1/622 (0.2%)		0/610 (0%)
Pulmonary Oedema	0/622 (0%)		1/610 (0.2%)
Surgical and medical procedures
Tumour Excision	1/622 (0.2%)		0/610 (0%)
Vascular disorders
Hypotension	6/622 (1%)		3/610 (0.5%)
Deep Vein Thrombosis	2/622 (0.3%)		2/610 (0.3%)
Embolism	2/622 (0.3%)		1/610 (0.2%)
Haemorrhage	1/622 (0.2%)		0/610 (0%)
Hypovolaemic Shock	1/622 (0.2%)		0/610 (0%)
Orthostatic Hypotension	1/622 (0.2%)		1/610 (0.2%)
Subclavian Vein Thrombosis	1/622 (0.2%)		0/610 (0%)
Venous Thrombosis	0/622 (0%)		1/610 (0.2%)
Other (Not Including Serious) Adverse Events
	Napabucasin + FOLFIRI ± Bevacizumab		FOLFIRI ± Bevacizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	619/622 (99.5%)		602/610 (98.7%)
Blood and lymphatic system disorders
Anaemia	154/622 (24.8%)		148/610 (24.3%)
Neutropenia	154/622 (24.8%)		165/610 (27%)
Thrombocytopenia	36/622 (5.8%)		24/610 (3.9%)
Leukopenia	32/622 (5.1%)		43/610 (7%)
Gastrointestinal disorders
Diarrhoea	526/622 (84.6%)		329/610 (53.9%)
Nausea	376/622 (60.5%)		308/610 (50.5%)
Vomiting	256/622 (41.2%)		180/610 (29.5%)
Abdominal Pain	255/622 (41%)		154/610 (25.2%)
Constipation	126/622 (20.3%)		173/610 (28.4%)
Stomatitis	92/622 (14.8%)		118/610 (19.3%)
Abdominal Pain Upper	63/622 (10.1%)		46/610 (7.5%)
Dyspepsia	56/622 (9%)		39/610 (6.4%)
Proctalgia	35/622 (5.6%)		20/610 (3.3%)
Abdominal Distension	34/622 (5.5%)		31/610 (5.1%)
General disorders
Fatigue	235/622 (37.8%)		219/610 (35.9%)
Asthenia	135/622 (21.7%)		119/610 (19.5%)
Pyrexia	117/622 (18.8%)		100/610 (16.4%)
Mucosal Inflammation	60/622 (9.6%)		90/610 (14.8%)
Oedema Peripheral	45/622 (7.2%)		48/610 (7.9%)
Malaise	43/622 (6.9%)		34/610 (5.6%)
Infections and infestations
Urinary Tract Infection	71/622 (11.4%)		40/610 (6.6%)
Upper Respiratory Tract Infection	44/622 (7.1%)		43/610 (7%)
Investigations
Neutrophil Count Decreased	149/622 (24%)		179/610 (29.3%)
Weight Decreased	106/622 (17%)		54/610 (8.9%)
White Blood Cell Count Decreased	87/622 (14%)		109/610 (17.9%)
Aspartate Aminotransferase Increased	75/622 (12.1%)		67/610 (11%)
Alanine Aminotransferase Increased	67/622 (10.8%)		57/610 (9.3%)
Blood Alkaline Phosphatase Increased	59/622 (9.5%)		35/610 (5.7%)
Platelet Count Decreased	42/622 (6.8%)		47/610 (7.7%)
Blood Bilirubin Increased	30/622 (4.8%)		32/610 (5.2%)
Metabolism and nutrition disorders
Decreased Appetite	233/622 (37.5%)		189/610 (31%)
Hypokalaemia	103/622 (16.6%)		57/610 (9.3%)
Dehydration	57/622 (9.2%)		36/610 (5.9%)
Hypoalbuminaemia	33/622 (5.3%)		29/610 (4.8%)
Musculoskeletal and connective tissue disorders
Back Pain	75/622 (12.1%)		84/610 (13.8%)
Nervous system disorders
Headache	85/622 (13.7%)		73/610 (12%)
Dizziness	59/622 (9.5%)		47/610 (7.7%)
Dysgeusia	46/622 (7.4%)		59/610 (9.7%)
Neuropathy Peripheral	32/622 (5.1%)		22/610 (3.6%)
Cholinergic Syndrome	20/622 (3.2%)		33/610 (5.4%)
Psychiatric disorders
Insomnia	54/622 (8.7%)		84/610 (13.8%)
Renal and urinary disorders
Chromaturia	70/622 (11.3%)		4/610 (0.7%)
Proteinuria	54/622 (8.7%)		44/610 (7.2%)
Respiratory, thoracic and mediastinal disorders
Cough	72/622 (11.6%)		75/610 (12.3%)
Epistaxis	60/622 (9.6%)		79/610 (13%)
Dyspnoea	57/622 (9.2%)		46/610 (7.5%)
Hiccups	41/622 (6.6%)		29/610 (4.8%)
Skin and subcutaneous tissue disorders
Alopecia	133/622 (21.4%)		159/610 (26.1%)
Rash	31/622 (5%)		41/610 (6.7%)
Palmar-Plantar Erythrodysaesthesia Syndrome	30/622 (4.8%)		33/610 (5.4%)
Vascular disorders
Hypertension	58/622 (9.3%)		65/610 (10.7%)

Limitations/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.