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First Line Metastatic Colorectal Cancer Therapy in Combination With FOLFOX

A Randomised, Double-blind, Multicentre Phase II/III Study to Compare the Efficacy of Cediranib (RECENTIN™, AZD2171) in Combination With 5-fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX), to the Efficacy of Bevacizumab in Combination With FOLFOX in Patients With Previously Untreated Metastatic Colorectal Cancer

Status
Completed
Phases
Phase 2Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00384176
Acronym
HORIZON III
Enrollment
1814
Registered
2006-10-05
Start date
2006-08-30
Completion date
2015-08-19
Last updated
2017-04-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Colorectal Cancer

Keywords

Metastatic Colorectal Cancer, RECENTIN

Brief summary

The purpose of this study is to see if Cediranib in combination with FOLFOX is effective in treating metastatic colorectal cancer and to see how it compares with Avastin (Bevacizumab) in combination with FOLFOX.

Interventions

DRUGCediranib

oral tablet once daily

DRUGBevacizumab

intravenous infusion

DRUG5-fluorouracil ( in FOLFOX)

intravenous infusion

DRUGLeucovorin (in FOLFOX)

intravenous infusion

DRUGOxaliplatin (in FOLFOX)

intravenous infusion

Sponsors

AstraZeneca
Lead SponsorINDUSTRY

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No

Inclusion criteria

* Clinical Diagnosis of colon or rectal cancer * No prior systemic therapy for metastatic disease. Any adjuvant/neoadjuvant oxaliplatin therapy must have been received \>12 months prior to study entry and adjuvant/neoadjuvant 5-FU must have been received \>6 months prior to study entry.

Exclusion criteria

* Prior treatment with a VEGF Inhibitor, including bevacizumab and cediranib. * Poorly controlled hypertension

Design outcomes

Primary

MeasureTime frameDescription
Progression Free SurvivalBaseline then at Weeks 8, 16, 24 and then every 12 weeks until progressionProgression is defined as the number of months from randomisation until progressive disease based on RECIST (progression of target lesions, clear progression of existing non-target lesions or the appearance of one or more new lesions) or death in the absence of progression.

Secondary

MeasureTime frameDescription
Overall SurvivalRandomisation until data cut-offNumber of months from randomisation to the date of death from any cause
Objective Response RateUp until data cut-offObjective response rate is Complete Response (CR) + Partial Response (PR) as defined below: CR = Disappearance of all target lesions. PR = At least a 30% decrease in the sum of longest diameters (LDs) of target lesions, taking as reference the baseline sum of LDs.
Duration of ResponseUp until data cut-off date of 15/11/2007Duration of Response is calculated as the time from the first recording of CR/PR until the patient progresses, regardless of whether the patient was still taking study medication. Only confirmed responses are included in the calculation. For patients who had not progressed, the end date used in the calculation of duration of response is the data cut-off date of 15th November 2009.
Percentage Change in Tumour SizeBaseline to Week 8Percentage change in tumour size from baseline to first RECIST assessment (Week 8) ((Week 8 - baseline)/baseline)\*100
Time to Worsening of Health Related Quality of Life (QOL) Based on the FACT Colorectal Symptom Index (FCSI)Baseline through to data cut-offTime to worsening of symptoms, as measured by the FACT colorectal symptom index (FCSI), will be defined as the time when a sustained clinically important deterioration in the total score from the FCSI has been recorded.

Countries

Australia, Austria, Belgium, Canada, Czechia, Egypt, Finland, France, Germany, Hungary, India, Israel, Italy, Latvia, Malta, Philippines, Poland, Russia, Slovakia, South Africa, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Vietnam

Participant flow

Recruitment details

Enrolled = 1814 though not all patient randomised. Randomised= Intent to treat (ITT): Cediranib 20mg 709, Cediranib 30mg 192 Bevacizumab 713; Safety: Cediranib 20mg 705, Cediranib 30mg 191 Bevacizumab 704

Pre-assignment details

Cediranib 30mg discontinued following Phase II, Cediranib 20mg chosen dose for comparing with Bevacizumab. 200 patients dropped prior to treatment. Study was set up as a phase II/III study. Participants were enrolled into both phases if they participated in both Phase II/III, but are only counted once in the Enrollment Number and in the Results.

Participants by arm

ArmCount
Cediranib 20 mg
Cediranib 20 mg/day + FOLFOX The FOLFOX regimen in this study was a modified FOLFOX6 regimen, repeated every 2 weeks: * Oxaliplatin 85 mg/m2 with leucovorin 400 mg/m2 (or equivalent folinic acid preparation) administered intravenously over 2 hours on Day 1 * 5-FU 400 mg/m2 bolus immediately after completion of the oxaliplatin infusion on Day 1, followed immediately by 5-FU 2400 mg/m2 administered by a continuous iv infusion over 46 hours.
709
Bevacizumab 5 mg/kg
Bevacizumab 5 mg/kg on Day 1 and every 2 weeks \+ FOLFOX The FOLFOX regimen in this study was a modified FOLFOX6 regimen, repeated every 2 weeks: * Oxaliplatin 85 mg/m2 with leucovorin 400 mg/m2 (or equivalent folinic acid preparation) administered intravenously over 2 hours on Day 1 * 5-FU 400 mg/m2 bolus immediately after completion of the oxaliplatin infusion on Day 1, followed immediately by 5-FU 2400 mg/m2 administered by a continuous iv infusion over 46 hours.
713
Cediranib 30 mg
Cediranib 30 mg/day + FOLFOX The FOLFOX regimen in this study was a modified FOLFOX6 regimen, repeated every 2 weeks: * Oxaliplatin 85 mg/m2 with leucovorin 400 mg/m2 (or equivalent folinic acid preparation) administered intravenously over 2 hours on Day 1 * 5-FU 400 mg/m2 bolus immediately after completion of the oxaliplatin infusion on Day 1, followed immediately by 5-FU 2400 mg/m2 administered by a continuous iv infusion over 46 hours.
192
Total1,614

Withdrawals & dropouts

PeriodReasonFG000FG001FG002
Overall StudyDeath239247105
Overall StudyDid not receive study treatment011
Overall StudyIncorrect enrol/elig crit not fulfilled230
Overall StudyLiver metastases, colon resec. planned100
Overall StudyLonger QTC as Visit 1100
Overall StudyLost to Follow-up16184
Overall StudyPhysician Decision020
Overall StudyToxicity of treatment100
Overall StudyWithdrawal by Subject524822

Baseline characteristics

CharacteristicCediranib 20 mgBevacizumab 5 mg/kgCediranib 30 mgTotal
Age, Continuous58.1 years
STANDARD_DEVIATION 11.37
59.0 years
STANDARD_DEVIATION 10.82
59.2 years
STANDARD_DEVIATION 10.59
58.6 years
STANDARD_DEVIATION 11.1
Sex: Female, Male
Female
297 Participants299 Participants73 Participants669 Participants
Sex: Female, Male
Male
412 Participants414 Participants119 Participants945 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
deaths
Total, all-cause mortality
— / —— / —— / —
other
Total, other adverse events
684 / 705187 / 191672 / 704
serious
Total, serious adverse events
275 / 70590 / 191231 / 704

Outcome results

Primary

Progression Free Survival

Progression is defined as the number of months from randomisation until progressive disease based on RECIST (progression of target lesions, clear progression of existing non-target lesions or the appearance of one or more new lesions) or death in the absence of progression.

Time frame: Baseline then at Weeks 8, 16, 24 and then every 12 weeks until progression

Population: Two cediranib doses (20 mg and 30 mg) were initially included in this study; however, it was intended that one dose would be selected for continuation. The decision was taken to continue with cediranib 20 mg. No statistical analyses were performed on the 30mg group.

ArmMeasureValue (MEDIAN)
Cediranib 20 mgProgression Free Survival9.9 Months
Bevacizumab 5 mg/kgProgression Free Survival10.3 Months
Secondary

Duration of Response

Duration of Response is calculated as the time from the first recording of CR/PR until the patient progresses, regardless of whether the patient was still taking study medication. Only confirmed responses are included in the calculation. For patients who had not progressed, the end date used in the calculation of duration of response is the data cut-off date of 15th November 2009.

Time frame: Up until data cut-off date of 15/11/2007

Population: Two cediranib doses (20 mg and 30 mg) were initially included in this study; however, it was intended that one dose would be selected for continuation. The decision was taken to continue with cediranib 20 mg. No statistical analyses were performed on the 30mg group.

ArmMeasureValue (MEDIAN)
Cediranib 20 mgDuration of Response8.6 Months
Bevacizumab 5 mg/kgDuration of Response9.6 Months
Secondary

Objective Response Rate

Objective response rate is Complete Response (CR) + Partial Response (PR) as defined below: CR = Disappearance of all target lesions. PR = At least a 30% decrease in the sum of longest diameters (LDs) of target lesions, taking as reference the baseline sum of LDs.

Time frame: Up until data cut-off

Population: Two cediranib doses (20 mg and 30 mg) were initially included in this study; however, it was intended that one dose would be selected for continuation. The decision was taken to continue with cediranib 20 mg. No statistical analyses were performed on the 30mg group.

ArmMeasureValue (NUMBER)
Cediranib 20 mgObjective Response Rate328 Participants
Bevacizumab 5 mg/kgObjective Response Rate337 Participants
Secondary

Overall Survival

Number of months from randomisation to the date of death from any cause

Time frame: Randomisation until data cut-off

Population: Two cediranib doses (20 mg and 30 mg) were initially included in this study; however, it was intended that one dose would be selected for continuation. The decision was taken to continue with cediranib 20 mg. No statistical analyses were performed on the 30mg group.

ArmMeasureValue (MEDIAN)
Cediranib 20 mgOverall Survival22.8 Months
Bevacizumab 5 mg/kgOverall Survival21.3 Months
Secondary

Percentage Change in Tumour Size

Percentage change in tumour size from baseline to first RECIST assessment (Week 8) ((Week 8 - baseline)/baseline)\*100

Time frame: Baseline to Week 8

Population: No statistical analyses were performed on the 30mg group. Patients had to have both a baseline and post-baseline (week 8) value to be included in the analysis. If patients did not have a week 8 assessment they were not included.

ArmMeasureValue (MEAN)Dispersion
Cediranib 20 mgPercentage Change in Tumour Size-23.2 Percentage change in tumour sizeStandard Deviation 21.8
Bevacizumab 5 mg/kgPercentage Change in Tumour Size-22.1 Percentage change in tumour sizeStandard Deviation 19.55
Secondary

Time to Worsening of Health Related Quality of Life (QOL) Based on the FACT Colorectal Symptom Index (FCSI)

Time to worsening of symptoms, as measured by the FACT colorectal symptom index (FCSI), will be defined as the time when a sustained clinically important deterioration in the total score from the FCSI has been recorded.

Time frame: Baseline through to data cut-off

ArmMeasureValue (MEDIAN)
Cediranib 20 mgTime to Worsening of Health Related Quality of Life (QOL) Based on the FACT Colorectal Symptom Index (FCSI)170 Days
Bevacizumab 5 mg/kgTime to Worsening of Health Related Quality of Life (QOL) Based on the FACT Colorectal Symptom Index (FCSI)245 Days

Source: ClinicalTrials.gov · Data processed: Mar 5, 2026