Colorectal Cancer, Neoplasm Metastasis
Conditions
Keywords
FOLFOX-4, Cetuximab, First-line mCRC, EGFR positive, metastatic CRC
Brief summary
This is an open label, randomized, controlled, multicenter phase II study comparing 5-FU/FA + oxaliplatin (FOLFOX-4) + cetuximab versus 5-FU/FA + oxaliplatin as first-line treatment for epidermal growth factor receptor (EGFR)-expressing mCRC.
Interventions
BIOLOGICALCetuximab
Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin folinic acid (FA) will be administered (at a dose of 200 mg/m\^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-Fluorouracil (5-FU) (as a bolus of 400 mg/m\^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m\^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops
DRUGOxaliplatin
Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m\^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m\^2/day IV over 2-4 minutes followed by 600 mg/m\^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* First-line mCRC * EGFR positive * Bi-dimensional measurable index lesion
Exclusion criteria
* Previous exposure to EGFR-targeting therapy * Previous oxaliplatin-based therapy * Previous chemotherapy for colorectal cancer except adjuvant treatment with progression of disease documented \> 6 months after end of adjuvant treatment * Radiotherapy * Surgery * Any other investigational drug in the 30 days before randomization * Brain metastasis and/or leptomeningeal disease * Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate - Independent Review Committee (IRC) | Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006 | The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified World Health Organisation (WHO) criteria) as assessed by an IRC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (KRAS Mutant Population) | Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007 | The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria) as assessed by an IRC. |
| Progression-free Survival Time | Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 01 Mar 2007 | Duration from randomization until radiological progression as assessed by an IRC (based on modified WHO criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment. |
| Progression-free Survival Time (KRAS Wild-Type Population) | Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 | Duration from randomization until radiological progression as assessed by an IRC (based on modified WHO criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment. |
| Progression-free Survival Time (KRAS Mutant Population) | Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 | Duration from randomization until radiological progression as assessed by an IRC (based on modified WHO criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment. |
| Overall Survival Time | Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 | Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. |
| Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) | Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007 | The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria) as assessed by an IRC. |
| Overall Survival Time (KRAS Mutant Population) | Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008 | Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. |
| Participants With No Residual Tumor After Metastatic Surgery | Time from first dose up to 30 days after the last dose of study treatment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008 | No residual tumor after on-study surgery for metastases. |
| Disease Control Rate (Cut Off Date 4 August 2006) | Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006 | The disease control rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments as assessed by IRC (based on modified WHO criteria). |
| Duration of Response | Time from first assessment of Complete Response or Partial Response to disease progression,death or last tumor assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 01 Mar 2007 | Time from first assessment of Complete Response or Partial Response to disease progression or death (within 60 days of last tumor assessment). Patients without event are censored on the date of last tumor assessment. Tumor assessments based on modified WHO criteria. |
| Safety - Number of Patients Experiencing Any Adverse Event | time from first dose up to 30 after last dose of study treatment, reported between day of first patient dose of study treatment, 27 Jul 2005, until cut-off date 30 Nov 2008 | Please refer to Adverse Events section for further details |
| Overall Survival Time (KRAS Wild-Type Population) | Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008 | Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. |
Countries
Austria, Belgium, France, Germany, Greece, Israel, Italy, Poland, Portugal, Romania, Russia, Spain, Ukraine
Participant flow
Recruitment details
First & last subject randomized: 27 Jul 2005 & 8 Mar 2006, respectively. Primary outcome and disease control rate cut-off dates 4 Aug 2006, others: 1 Mar 2007; except overall survival, KRAS overall survival and KRAS progression-free survival outcomes, metastatic surgery outcome and adverse events: 30 Nov 2008.
Pre-assignment details
629 subjects were prescreened, of whom 344 subjects were randomised. 338 subjects (Safety Population) received treatment. One subject was erroneously randomized, and was excluded from the ITT population (337 subjects).
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab Plus FOLFOX-4 Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m\^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m\^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m\^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects. | 169 |
| FOLFOX-4 Alone 5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m\^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m\^2/day IV over 2-4 minutes followed by 600 mg/m\^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects. | 168 |
| Total | 337 |
Baseline characteristics
| Characteristic | Cetuximab Plus FOLFOX-4 | FOLFOX-4 Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 73 Participants | 59 Participants | 132 Participants |
| Age, Categorical Between 18 and 65 years | 96 Participants | 109 Participants | 205 Participants |
| Age, Continuous | 62.0 years | 60.0 years | 61.0 years |
| Region of Enrollment Austria | 16 participants | 9 participants | 25 participants |
| Region of Enrollment Belgium | 12 participants | 6 participants | 18 participants |
| Region of Enrollment France | 3 participants | 12 participants | 15 participants |
| Region of Enrollment Germany | 14 participants | 22 participants | 36 participants |
| Region of Enrollment Israel | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Italy | 8 participants | 6 participants | 14 participants |
| Region of Enrollment Poland | 30 participants | 31 participants | 61 participants |
| Region of Enrollment Portugal | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Romania | 18 participants | 13 participants | 31 participants |
| Region of Enrollment Russian Federation | 25 participants | 24 participants | 49 participants |
| Region of Enrollment Spain | 19 participants | 16 participants | 35 participants |
| Region of Enrollment Ukraine | 24 participants | 25 participants | 49 participants |
| Sex: Female, Male Female | 80 Participants | 76 Participants | 156 Participants |
| Sex: Female, Male Male | 89 Participants | 92 Participants | 181 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 170 / 170 | 165 / 168 |
| serious Total, serious adverse events | 61 / 170 | 43 / 168 |
Outcome results
Primary
Best Overall Response Rate - Independent Review Committee (IRC)
The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified World Health Organisation (WHO) criteria) as assessed by an IRC.
Time frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006
Population: Primary analysis on the Intent to Treat (ITT) population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Best Overall Response Rate - Independent Review Committee (IRC) | 45.6 percentage of participants |
| FOLFOX-4 Alone | Best Overall Response Rate - Independent Review Committee (IRC) | 35.7 percentage of participants |
Comparison: Assuming a difference in rate of best confirmed response of at least 20% between the 2 treatments, ie an approximately 70% response rate under cetuximab plus FOLFOX-4 \& 50% under FOLFOX-4 alone for the stratum with ECOG PS0-1 \& 66% and 45% respectively for the ECOG PS2 stratum, the common OddsR over the strata was expected to be 2.33. A sample size of approximately 146/group was calculated as necessary to detect a significant overall response of at least 2.33 at level α=0.05 with a power of 90%p-value: 0.06495% CI: [0.975, 2.335]stratified Cochran-Mantel-Haenszel test
Secondary
Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population)
The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria) as assessed by an IRC.
Time frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007
Population: KRAS Wild-Type population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) | 57.3 percentage of participants |
| FOLFOX-4 Alone | Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) | 34.0 percentage of participants |
p-value: 0.002795% CI: [1.38, 4.717]stratified Cochran-Mantel-Haenszel test
Secondary
Best Overall Response Rate (KRAS Mutant Population)
The best overall response rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria) as assessed by an IRC.
Time frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007
Population: KRAS Mutant population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Best Overall Response Rate (KRAS Mutant Population) | 33.8 percentage of participants |
| FOLFOX-4 Alone | Best Overall Response Rate (KRAS Mutant Population) | 52.5 percentage of participants |
p-value: 0.02995% CI: [0.228, 0.924]stratified Cochran-Mantel-Haenszel test
Secondary
Disease Control Rate (Cut Off Date 4 August 2006)
The disease control rate is defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments as assessed by IRC (based on modified WHO criteria).
Time frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006
Population: Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Disease Control Rate (Cut Off Date 4 August 2006) | 85.2 percentage of participants |
| FOLFOX-4 Alone | Disease Control Rate (Cut Off Date 4 August 2006) | 81.0 percentage of participants |
Secondary
Duration of Response
Time from first assessment of Complete Response or Partial Response to disease progression or death (within 60 days of last tumor assessment). Patients without event are censored on the date of last tumor assessment. Tumor assessments based on modified WHO criteria.
Time frame: Time from first assessment of Complete Response or Partial Response to disease progression,death or last tumor assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 01 Mar 2007
Population: Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Duration of Response | 9.0 months |
| FOLFOX-4 Alone | Duration of Response | 5.7 months |
Secondary
Overall Survival Time
Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.
Time frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008
Population: Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Overall Survival Time | 18.3 months |
| FOLFOX-4 Alone | Overall Survival Time | 18.0 months |
p-value: 0.90595% CI: [0.791, 1.303]Stratified log rank
Secondary
Overall Survival Time (KRAS Mutant Population)
Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.
Time frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008
Population: KRAS Mutant population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Overall Survival Time (KRAS Mutant Population) | 13.4 months |
| FOLFOX-4 Alone | Overall Survival Time (KRAS Mutant Population) | 17.5 months |
p-value: 0.200495% CI: [0.873, 1.906]Stratified log rank
Secondary
Overall Survival Time (KRAS Wild-Type Population)
Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.
Time frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008
Population: KRAS Wild-Type population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Overall Survival Time (KRAS Wild-Type Population) | 22.8 months |
| FOLFOX-4 Alone | Overall Survival Time (KRAS Wild-Type Population) | 18.5 months |
p-value: 0.385495% CI: [0.599, 1.219]Stratified log rank
Secondary
Participants With No Residual Tumor After Metastatic Surgery
No residual tumor after on-study surgery for metastases.
Time frame: Time from first dose up to 30 days after the last dose of study treatment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008
Population: Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Participants With No Residual Tumor After Metastatic Surgery | 8 participants |
| FOLFOX-4 Alone | Participants With No Residual Tumor After Metastatic Surgery | 4 participants |
Secondary
Progression-free Survival Time
Duration from randomization until radiological progression as assessed by an IRC (based on modified WHO criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 01 Mar 2007
Population: Primary analysis on ITT population i.e. all randomized subjects who have received at least one dose of randomized treatment (allocation to treatment groups as randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Progression-free Survival Time | 7.2 months |
| FOLFOX-4 Alone | Progression-free Survival Time | 7.2 months |
p-value: 0.61795% CI: [0.705, 1.23]Stratified Log Rank
Secondary
Progression-free Survival Time (KRAS Mutant Population)
Duration from randomization until radiological progression as assessed by an IRC (based on modified WHO criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008
Population: KRAS Mutant population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Progression-free Survival Time (KRAS Mutant Population) | 5.5 months |
| FOLFOX-4 Alone | Progression-free Survival Time (KRAS Mutant Population) | 8.6 months |
p-value: 0.015395% CI: [1.104, 2.679]Stratified Log Rank
Secondary
Progression-free Survival Time (KRAS Wild-Type Population)
Duration from randomization until radiological progression as assessed by an IRC (based on modified WHO criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008
Population: KRAS Wild-Type population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Progression-free Survival Time (KRAS Wild-Type Population) | 8.3 months |
| FOLFOX-4 Alone | Progression-free Survival Time (KRAS Wild-Type Population) | 7.2 months |
p-value: 0.006495% CI: [0.375, 0.856]Stratified Log Rank
Secondary
Safety - Number of Patients Experiencing Any Adverse Event
Please refer to Adverse Events section for further details
Time frame: time from first dose up to 30 after last dose of study treatment, reported between day of first patient dose of study treatment, 27 Jul 2005, until cut-off date 30 Nov 2008
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus FOLFOX-4 | Safety - Number of Patients Experiencing Any Adverse Event | 170 participants |
| FOLFOX-4 Alone | Safety - Number of Patients Experiencing Any Adverse Event | 165 participants |