Study of Enzastaurin With 5-Fluorouracil/Leucovorin (5-FU... | NCT00612586

ID	Type	Description	Link
H6Q-MC-S064	Other Identifier	Eli Lilly and Company

Name	Class
Roche Pharma AG	INDUSTRY

Label	Type	Description	Intervention Names
Enzastaurin + 5-FU/LV + Bev	Experimental	5-fluorouracil/leucovorin (5-FU/LV) plus bevacizumab (Bev) in combination with enzastaurin	Drug: Enzastaurin Drug: Leucovorin (LV) Drug: 5-fluorouracil (5-FU) Drug: Bevacizumab (Bev)
Placebo + 5-FU/LV + Bev	Placebo Comparator	5-fluorouracil/leucovorin (5-FU/LV) plus bevacizumab (Bev) in combination with placebo	Drug: Placebo Drug: Leucovorin (LV) Drug: 5-fluorouracil (5-FU) Drug: Bevacizumab (Bev)

Name	Type	Description	Arm Group Labels	Other Names
Enzastaurin	Drug	1125 milligram (mg) loading dose, then 250 mg twice daily, oral up to 1 year (yr) or until progressive disease	Enzastaurin + 5-FU/LV + Bev

Measure	Description	Time Frame
Progression Free Survival (PFS)	PFS was defined as the time from randomization to the first observation of disease progression or death due to any cause. Progressive disease was determined using a modified version of Response Evaluation Criteria in Solid Tumor (RECIST) Assessment and was defined as at least a 20% increase in sum of longest diameter of target lesions. Time to disease progression was censored at the date of death if death was due to other cause.	Randomization to measured progressive disease or death up to 17.2 months

Measure	Description	Time Frame
Overall Survival (OS)	OS was the duration from enrollment to death due to any cause. For participants who are alive, OS is censored at the last contact.	Randomization up to 22.8 months
Number of Participants With Adverse Events (AEs)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologic diagnosis of locally advanced or metastatic colorectal cancer (CRC) that is not curable. The histology types to be included are adenocarcinoma, mucinous adenocarcinoma, signet ring, and undifferentiated. Patients with neuroendocrine carcinomas will be excluded.
Received 6 cycles (3 months [12 weeks]) of first-line therapy with FOLFOX or FOLFIRI, plus bevacizumab for metastatic CRC. Patients have received at least 5 cycles with bevacizumab. Patients who received 6 cycles of first-line therapy with FOLFOX or FOLFIRI, plus bevacizumab for recurrent CRC that has relapsed at least 12 months after completion of adjuvant therapy will also be included. All standard FOLFOX (FOLFIRI) regimens given on a biweekly schedule will be permitted; however, 21-day regimens will not be allowed.
No more than 4 weeks may pass between the end of first-line therapy (that is, Day 14 of Cycle 6) and randomization.
Documented evidence of tumor response of complete response (CR), partial response (PR), or stable disease (SD) by computed tomography (CT) scan or magnetic resonance imaging (MRI). Confirmation of response is not required.

Exclusion Criteria:

Are unable to swallow tablets.
Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
Have known central nervous system metastases.
Are receiving concurrent administration of any other antitumor therapy.
Patients who have significant heart, liver, kidney, or psychiatric disease or have an active infection

Name	Affiliation	Role
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)	Eli Lilly and Company	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.		Memphis	Tennessee	38138

PubMed Identifier	Type	Citation	Retractions
22213153	Derived	Wolff RA, Fuchs M, Di Bartolomeo M, Hossain AM, Stoffregen C, Nicol S, Heinemann V. A double-blind, randomized, placebo-controlled, phase 2 study of maintenance enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line therapy for metastatic colorectal cancer. Cancer. 2012 Sep 1;118(17):4132-8. doi: 10.1002/cncr.26692. Epub 2011 Dec 27.

ID	Title	Description
FG000	Enzastaurin + 5-FU/LV + Bev	Enzastaurin: Loading dose of 1125 milligrams (mg) orally, 3 times during Day 1 of Cycle 1 (14-day cycle); 500 mg orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. Leucovorin (LV): 400 mg per meter squared (mg/m^2) intravenously (IV) on Day 1 of each 14-day cycle, followed by 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bevacizumab (Bev): 5 milligrams/kilogram (mg/kg) IV. First-line therapy for metastatic colorectal cancer (CRC) received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-FU, and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00062.55± 10.90 BG00162.49± 9.48 BG00262.52± 10.16

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00021 BG00121 BG002

Race/Ethnicity, Customized

Count of Participants

Participants

Title

Denominators

Categories

Caucasian

Title	Measurements
	BG00055 BG00154 BG002

Region of Enrollment

Count of Participants

Participants

Title

Denominators

Categories

Austria

Title	Measurements
	BG0005 BG0018 BG002

Eastern Cooperative Oncology Group (ECOG) Performance Status

ECOG a scale to rate participants' activity status: 0-fully active; 1-Ambulatory, Restricted Strenuous Activity; 2-Ambulatory, No Work Activities; 3-Partially Confined to Bed, Limited Self Care; 4-Completely Disabled.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
	BG00042 BG001

Initial Pathological Diagnosis

Count of Participants

Participants

Title

Denominators

Categories

Adenocarcinoma, Mucinous, Not Otherwise Specified

Title	Measurements
	BG0003 BG0014 BG002

Stage of Disease at Study Entry

Tumor Stage (St) I-in inner lining or muscle layer of bowel wall; St IIa-in outer layer of bowel wall or invades adjacent tissues; St IIb- invaded adjacent organs or penetrates peritoneum; St IIIa- in inner lining or muscle layer of bowel wall and has spread to 1-3 nearby nodes; St IIIb- in outer layer of bowel wall or invades adjacent tissue or organs, and has spread to 1-3 nearby nodes; St IIIc-in outer layer of bowel wall or invades adjacent tissue or organs, and has spread to ≥ 4 nearby nodes; St IV- has spread to distant sites. Tumor stage is missing for some participants.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
	BG0000 BG001

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Progression Free Survival (PFS)

PFS was defined as the time from randomization to the first observation of disease progression or death due to any cause. Progressive disease was determined using a modified version of Response Evaluation Criteria in Solid Tumor (RECIST) Assessment and was defined as at least a 20% increase in sum of longest diameter of target lesions. Time to disease progression was censored at the date of death if death was due to other cause.

Intent-to-Treat (ITT) Population: All randomized participants.

Posted

Median

95% Confidence Interval

months

Randomization to measured progressive disease or death up to 17.2 months

ID	Title	Description
OG000	Enzastaurin + 5-FU/LV + Bev	Enzastaurin: Loading dose of 1125 mg orally, 3 times during Day 1 of Cycle 1 (14-day cycle); 500 mg orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for metastatic CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-FU, and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.
OG001	Placebo + 5FU/LV + Bev	Placebo: Orally 3 times during Day 1 of Cycle 1 (14-day cycle); orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) FOLFOX or FOLFIRI, plus Bev.

Units	Counts
Participants	OG00058 OG00159

Title

Denominators

Categories

Title	Measurements
	OG0005.8(4.4 to 7.8) OG0018.1(6.8 to 12.1)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Log Rank		0.8956	One sided													Superiority or Other (legacy)

Secondary

Overall Survival (OS)

OS was the duration from enrollment to death due to any cause. For participants who are alive, OS is censored at the last contact.

ITT Population: All randomized participants; Number of participants censored was 54 in Placebo + 5-FU/LV + Bev treatment group.

Posted

Median

95% Confidence Interval

months

Randomization up to 22.8 months

ID	Title	Description
OG000	Enzastaurin + 5-FU/LV + Bev	Enzastaurin: Loading dose of 1125 mg orally, 3 times during Day 1 of Cycle 1 (14-day cycle); 500 mg orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for metastatic CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-FU, and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.
OG001	Placebo + 5FU/LV + Bev	Placebo: Orally 3 times during Day 1 of Cycle 1 (14-day cycle); orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) FOLFOX or FOLFIRI, plus Bev.

Secondary

Number of Participants With Adverse Events (AEs)

A summary of serious and all other non-serious AEs is located in the Reported Adverse Event module.

Safety Population: All randomized participants who received at least 1 dose of study drug.

Posted

Count of Participants

Participants

Randomization up to 17.2 months

ID	Title	Description
OG000	Enzastaurin + 5-FU/LV + Bev	Enzastaurin: Loading dose of 1125 mg orally, 3 times during Day 1 of Cycle 1 (14-day cycle); 500 mg orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for metastatic CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-FU, and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.
OG001	Placebo + 5FU/LV +Bev	Placebo: Orally 3 times during Day 1 of Cycle 1 (14-day cycle); orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) FOLFOX or FOLFIRI, plus Bev.

Secondary

Overall Survival (OS) From Start of First Line Therapy

OS was the duration from first line therapy to death due to any cause. For participants who are alive, OS is censored at the last contact.

ITT Population: All randomized participants; Number of participants censored were 45 in Enzastaurin + 5-FU/LV + Bev treatment group and 54 in Placebo + 5-FU/LV + Bev treatment group.

Posted

Median

95% Confidence Interval

months

Start of first line therapy (approximately 3 months prior to randomization) to date of death from any cause up to 27 months post randomization

ID	Title	Description
OG000	Enzastaurin + 5-FU/LV + Bev	Enzastaurin: Loading dose of 1125 mg orally, 3 times during Day 1 of Cycle 1 (14-day cycle); 500 mg orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for metastatic CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-FU, and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.
OG001	Placebo + 5FU/LV + Bev	Placebo: Orally 3 times during Day 1 of Cycle 1 (14-day cycle); orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) FOLFOX or FOLFIRI, plus Bev.

Secondary

PFS From Start of First Line Therapy

PFS was defined as the time from first line therapy to the first observation of disease progression or death due to any cause. Progressive disease was determined using a modified version of RECIST Assessment and was defined as at least a 20% increase in sum of longest diameter of target lesions. Time to disease progression was censored at the date of death if death was due to other cause.

ITT Population: All randomized participants.

Posted

Median

95% Confidence Interval

months

Start of first line therapy to measured progressive disease or death up to 24 months

ID	Title	Description
OG000	Enzastaurin + 5-FU/LV + Bev	Enzastaurin: Loading dose of 1125 mg orally, 3 times during Day 1 of Cycle 1 (14-day cycle); 500 mg orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for metastatic CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-FU, and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.
OG001	Placebo + 5FU/LV + Bev	Placebo: Orally 3 times during Day 1 of Cycle 1 (14-day cycle); orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) FOLFOX or FOLFIRI, plus Bev.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Arrhythmia	Cardiac disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Abdominal hernia	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Abdominal pain lower	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Colonic obstruction	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0010 events0 affected58 at risk
Ileus	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Stomatitis	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0002 events2 affected57 at risk EG0010 events0 affected58 at risk
Subileus	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Vomiting	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Mucosal inflammation	General disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Pyrexia	General disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Catheter related infection	Infections and infestations	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Device related infection	Infections and infestations	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Pneumonia	Infections and infestations	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Staphylococcal bacteraemia	Infections and infestations	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Stent malapposition	Injury, poisoning and procedural complications	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Alanine aminotransferase increased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Aspartate aminotransferase increased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Hypertriglyceridaemia	Metabolism and nutrition disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Joint range of motion decreased	Musculoskeletal and connective tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Intracranial venous sinus thrombosis	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Syncope	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0010 events0 affected58 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG0004 events4 affected57 at risk EG0010 events0 affected58 at risk
Hypertensive emergency	Vascular disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk
Subclavian vein thrombosis	Vascular disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0011 events1 affected58 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (12.1)	Systematic Assessment	EG0007 events6 affected57 at risk EG0016 events5 affected58 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA (12.1)	Systematic Assessment	EG0004 events3 affected57 at risk EG0011 events1 affected58 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA (12.1)	Systematic Assessment	EG00014 events10 affected57 at risk EG00110 events7 affected58 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (12.1)	Systematic Assessment	EG00011 events10 affected57 at risk EG00112 events8 affected58 at risk
Eye irritation	Eye disorders	MedDRA (12.1)	Systematic Assessment	EG0002 events2 affected57 at risk EG0013 events3 affected58 at risk
Lacrimation increased	Eye disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0013 events3 affected58 at risk
Vision blurred	Eye disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0013 events3 affected58 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events3 affected57 at risk EG0010 events0 affected58 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG00011 events10 affected57 at risk EG0015 events5 affected58 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0004 events3 affected57 at risk EG0016 events5 affected58 at risk
Constipation	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG00015 events13 affected57 at risk EG0015 events5 affected58 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG00025 events19 affected57 at risk EG00133 events22 affected58 at risk
Dysphagia	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0010 events0 affected58 at risk
Faeces discoloured	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events5 affected57 at risk EG0011 events1 affected58 at risk
Flatulence	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0006 events6 affected57 at risk EG0013 events3 affected58 at risk
Gingival bleeding	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0004 events4 affected57 at risk EG0010 events0 affected58 at risk
Nausea	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG00018 events15 affected57 at risk EG00127 events15 affected58 at risk
Oral pain	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0006 events5 affected57 at risk EG0011 events1 affected58 at risk
Stomatitis	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events5 affected57 at risk EG0014 events4 affected58 at risk
Vomiting	Gastrointestinal disorders	MedDRA (12.1)	Systematic Assessment	EG0007 events7 affected57 at risk EG00115 events10 affected58 at risk
Asthenia	General disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0010 events0 affected58 at risk
Chills	General disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0011 events1 affected58 at risk
Fatigue	General disorders	MedDRA (12.1)	Systematic Assessment	EG00029 events24 affected57 at risk EG00129 events23 affected58 at risk
Mucosal inflammation	General disorders	MedDRA (12.1)	Systematic Assessment	EG00012 events9 affected57 at risk EG00112 events9 affected58 at risk
Pain	General disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0010 events0 affected58 at risk
Pyrexia	General disorders	MedDRA (12.1)	Systematic Assessment	EG0007 events6 affected57 at risk EG0018 events7 affected58 at risk
Nasopharyngitis	Infections and infestations	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0013 events2 affected58 at risk
Sinusitis	Infections and infestations	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0011 events1 affected58 at risk
Urinary tract infection	Infections and infestations	MedDRA (12.1)	Systematic Assessment	EG0005 events5 affected57 at risk EG0013 events3 affected58 at risk
Alanine aminotransferase increased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0005 events5 affected57 at risk EG0017 events6 affected58 at risk
Aspartate aminotransferase increased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0004 events4 affected57 at risk EG0015 events5 affected58 at risk
Blood creatinine increased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0002 events2 affected57 at risk EG0013 events3 affected58 at risk
Haemoglobin decreased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0006 events6 affected57 at risk EG0012 events2 affected58 at risk
Neutrophil count decreased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0012 events2 affected58 at risk
Urine colour abnormal	Investigations	MedDRA (12.1)	Systematic Assessment	EG0007 events7 affected57 at risk EG0010 events0 affected58 at risk
Weight decreased	Investigations	MedDRA (12.1)	Systematic Assessment	EG0005 events5 affected57 at risk EG0010 events0 affected58 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA (12.1)	Systematic Assessment	EG00010 events9 affected57 at risk EG0017 events7 affected58 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0012 events2 affected58 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events5 affected57 at risk EG0013 events3 affected58 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0011 events1 affected58 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0010 events0 affected58 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA (12.1)	Systematic Assessment	EG0001 events1 affected57 at risk EG0014 events4 affected58 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0007 events7 affected57 at risk EG0016 events5 affected58 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0016 events6 affected58 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0004 events3 affected57 at risk EG0013 events3 affected58 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events5 affected57 at risk EG0013 events3 affected58 at risk
Dizziness	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0006 events6 affected57 at risk EG00111 events6 affected58 at risk
Dysgeusia	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0002 events2 affected57 at risk EG0013 events3 affected58 at risk
Headache	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG00017 events10 affected57 at risk EG00112 events8 affected58 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events4 affected57 at risk EG0011 events1 affected58 at risk
Paraesthesia	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events4 affected57 at risk EG0014 events2 affected58 at risk
Peripheral sensory neuropathy	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0007 events6 affected57 at risk EG0018 events8 affected58 at risk
Polyneuropathy	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0014 events4 affected58 at risk
Somnolence	Nervous system disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events4 affected57 at risk EG0011 events1 affected58 at risk
Anxiety	Psychiatric disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0011 events1 affected58 at risk
Depression	Psychiatric disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0011 events1 affected58 at risk
Insomnia	Psychiatric disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0013 events3 affected58 at risk
Chromaturia	Renal and urinary disorders	MedDRA (12.1)	Systematic Assessment	EG0004 events4 affected57 at risk EG0010 events0 affected58 at risk
Proteinuria	Renal and urinary disorders	MedDRA (12.1)	Systematic Assessment	EG0006 events6 affected57 at risk EG0014 events4 affected58 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG00017 events13 affected57 at risk EG00112 events11 affected58 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG0007 events6 affected57 at risk EG0015 events5 affected58 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG00020 events16 affected57 at risk EG00116 events13 affected58 at risk
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events4 affected57 at risk EG0014 events4 affected58 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG0004 events4 affected57 at risk EG0012 events2 affected58 at risk
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA (12.1)	Systematic Assessment	EG0002 events2 affected57 at risk EG0016 events6 affected58 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0005 events5 affected57 at risk EG0016 events5 affected58 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0006 events6 affected57 at risk EG0014 events4 affected58 at risk
Nail disorder	Skin and subcutaneous tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0002 events2 affected57 at risk EG0013 events3 affected58 at risk
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA (12.1)	Systematic Assessment	EG00016 events9 affected57 at risk EG00118 events14 affected58 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0000 events0 affected57 at risk EG0014 events4 affected58 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0009 events8 affected57 at risk EG0015 events5 affected58 at risk
Skin exfoliation	Skin and subcutaneous tissue disorders	MedDRA (12.1)	Systematic Assessment	EG0003 events3 affected57 at risk EG0012 events2 affected58 at risk
Hypertension	Vascular disorders	MedDRA (12.1)	Systematic Assessment	EG0007 events7 affected57 at risk EG00117 events13 affected58 at risk

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D004066	Digestive System Diseases
D005767	Gastrointestinal Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases
D012002	Rectal Diseases

ID	Term
D005575	Formyltetrahydrofolates
D013763	Tetrahydrofolates
D005492	Folic Acid
D011622	Pterins
D011621	Pteridines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds
D003067	Coenzymes
D045762	Enzymes and Coenzymes
D014498	Uracil
D011744	Pyrimidinones
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
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

ID	Title	Description
BG000	Enzastaurin + 5-FU/LV + Bev	Enzastaurin: Loading dose of 1125 mg orally, 3 times during Day 1 of Cycle 1 (14-day cycle); 500 mg orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. LV: 400 mg/m^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bev: 5 mg/kg IV. First-line therapy for metastatic CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-FU, and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.
BG001	Placebo + 5-FU/LV + Bev	Placebo: administered orally 3 times during Day 1 of Cycle 1 (14 day cycle); placebo administered orally twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. Leucovorin (LV): 400 mg/m^2 administered by IV on Day 1 of each 14 day cycle, followed by 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bevacizumab (Bev): 5 milligrams/kilogram (mg/kg) IV. First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Enzastaurin + 5-FU/LV Plus Bevacizumab	Enzastaurin: loading dose of 1125 mg administered orally 3 times during Day 1 of Cycle 1 (14 day cycle); 500 mg administered orally twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. Leucovorin (LV): 400 mg per meter squared (mg/m^2) administered by IV on Day 1 of each 14 day cycle, followed by 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bevacizumab (Bev): 5 milligrams/kilogram (mg/kg) IV. First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.			15	57	53	57
EG001	Placebo + 5FU/LV + Bevacizumab	Placebo: administered orally 3 times during Day 1 of Cycle 1 (14 day cycle); placebo administered orally twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles. Leucovorin (LV): 400 mg/m^2 administered by IV on Day 1 of each 14 day cycle, followed by 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus then 2400 mg/m^2 IV over 46 hours, plus Bevacizumab (Bev): 5 milligrams/kilogram (mg/kg) IV. First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev.			11	58	52	58

ID	Term
C504878	enzastaurin
D002955	Leucovorin
D005472	Fluorouracil
D000068258	Bevacizumab