Metastatic Colorectal Cancer
Conditions
Keywords
mCRC
Brief summary
This is an open-label, non-randomized, multicenter Phase II study evaluating folinic acid + fluorouracil + irinotecan (FOLFIRI) plus cetuximab (Erbitux) or folinic acid + fluorouracil + oxaliplatin (FOLFOX) plus cetuximab as first-line therapy of patients with KRAS wild-type metastatic colorectal cancer. Only subjects with k-ras oncogene (KRAS) wild-type tumors are eligible. Efficacy will be assessed every 8 weeks. Treatment will be continued until progressive disease or unacceptable adverse events occur. After the end of study treatment, information on further anticancer treatment and survival will be collected every 3 months.
Interventions
DRUGCetuximab
Cetuximab will be administered intravenously at a dose of 500 milligram per square meter (mg/m\^2) biweekly on Day 1 of 14 days treatment cycle until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent.
DRUGFOLFIRI
Irinotecan will be administered intravenously at a dose of 180 mg/m\^2 along with folinic acid administration intravenously at a dose of 400 mg/m\^2 (racemic) or 200 mg/m\^2 (L-form) and 5-fluorouracil will be administered intravenously at a dose of 400 mg/m\^2 bolus followed by a 46-hour continuous infusion of 2,400 mg/m\^2 given biweekly until disease progression, death, or consent withdrawal.
DRUGFOLFOX
Oxaliplatin will be administered intravenously at a dose of 100 mg/m\^2 along with folinic acid administration intravenously at a dose of 400 mg/m\^2 (racemic) or 200 mg/m\^2 (L-form) and 5-fluorouracil administration intravenously at a dose of 400 mg/m\^2 bolus followed by a 46-hour continuous infusion of 2,400 mg/m\^2 given biweekly until disease progression, death, or consent withdrawal.
Sponsors
Merck Pte. Ltd., Singapore
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Signed written informed consent * Inpatient or outpatient subjects, 18 years of age * Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum * Metastatic disease (M1) * Life expectancy of at least 12 weeks * Presence of at least 1 measurable index lesion (not lie in an irradiated area) by computed tomography (CT) scan or magnetic resonance imaging (MRI) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry * Effective contraception for both male and female subjects if the risk of conception exists * White blood cell count greater than or equal to (\>=) 3,000 per cubic millimeter (/mm\^3) with neutrophils \>=1,500/mm3, platelet count \>=100,000/mm3, hemoglobin \>=5.6 millimole per liter (mmol/L) (9 gram per deciliter \[g/dL\]) * Total bilirubin less than or equal to (\<=) 1.5 x upper reference range * Aspartate aminotransferase (AST) \<=2.5 x upper reference range, or \<=5 x upper reference range in case of liver metastasis * Serum creatinine \<=1.5 x upper reference range * Recovery from relevant toxicity to previous treatment before study entry * KRAS wild-type status of tumor tissue
Exclusion criteria
* Previous chemotherapy for colorectal cancer except adjuvant treatment if terminated \>6 months before the start of treatment in this study * Radiotherapy, surgery (excluding prior diagnostic biopsy) or any investigational drug in the 30 days before the start of treatment in this study * Concurrent chronic systemic immune therapy, targeted therapy, anti-vascular endothelial growth factor (VEGF) therapy, or epidermal growth factor receptor (EGFR-) pathway targeting therapy not indicated in this study protocol * Concurrent hormone therapy not indicated in this study protocol except for physiologic replacement or contraception * Known hypersensitivity reaction to any of the components of study treatments * Pregnancy (absence to be confirmed by beta human choriongonadotrophin \[beta-hCG\] test) or lactation period * Brain metastasis and/or leptomeningeal disease (known or suspected) * Clinically relevant coronary artery disease, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia * Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease * Peripheral neuropathy \> grade 1 * Previous malignancy other than colorectal cancer in the last 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix * Known alcohol or drug abuse * Medical or psychological conditions that would not permit the patient to complete the study or sign informed consent * Participation in another clinical study within the past 30 days * Significant disease which, in the investigator's opinion, would exclude the patient from the study * Legal incapacity or limited legal capacity * KRAS mutated status of tumor tissue
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Best Overall Confirmed Response Rate (BORR) | From the start of the trial until disease progression, death or last tumor assessment, reported between day of first subject recruited until data cut-off date (31 May 2012) | Response rate was defined as the percentage of subjects with BORR (confirmed complete response \[CR\] or partial response \[PR\]) according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. As per RECIST v 1.0 criteria for target lesions and assessed by magnetic resonance imaging (MRI): CR = disappearance of all target lesions; PR = at least 30 percent (%) decrease in the sum of the longest diameter of target lesions. Response rate will be assessed every 8 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Time | From the start of the trial until disease progression, death or last tumor assessment, reported between day of first subject recruited and until data cut-off date (31 March 2014) | PFS time was defined as the time from first administration of study drug until first observation of disease progression or death when death occurs within 90 days of the last tumor assessment or first study drug dose whichever occurred. |
| Overall Survival (OS) Time | From the start of the trial until disease progression, death or last tumor assessment, reported between day of first subject recruited and until data cut-off date (31 March 2014) | OS time was defined as the time from first administration of study drug until date of death, assessed up to 5 years. OS time was censored if the subject was found to be alive on the last date of the assessment. |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | From the start of the trial until disease progression, death or last tumor assessment, reported between day of first subject recruited and until data cut-off date (31 March 2014) | An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
Countries
Singapore
Participant flow
Recruitment details
First/Last subject (informed consent): February 2009/June 2012. Study completion date: April 2014. Clinical data cut-off: 31 March 2014. Subjects were recruited in 12 countries (Australia, China, Hong Kong, India, Indonesia, Korea, Malaysia, Singapore, Pakistan, Philippines, Taiwan and Thailand) across the globe in 43 centers.
Pre-assignment details
Enrolled: 661 screened for eligibility; 372 were excluded (mainly non-fulfillment of inclusion or exclusion criteria). 289 subjects were assigned to the treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab Plus FOLFIRI Cetuximab was administered intravenously at a dose of 500 milligram per square meter (mg/m\^2) biweekly followed by Folfiri (Irinotecan administered intravenously at a dose of 180 mg/m\^2 ,folinic acid administered intravenously at a dose of 400 mg/m\^2 (racemic) or 200 mg/m\^2 (L-form), 5-fluorouracil administered intravenously at a dose of 400 mg/m\^2 bolus followed by a 46-hour continuous infusion at a dose of 2,400 mg/m\^2) on Day 1 of 14 days treatment cycle until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. | 101 |
| Cetuximab Plus FOLFOX Cetuximab was administered intravenously at a dose of 500 milligram per square meter (mg/m\^2) biweekly followed by Folfox (Oxaliplatin administered intravenously at a dose of 180 mg/m\^2, folinic acid administered intravenously at a dose of 400 mg/m\^2 (racemic) or 200 mg/m\^2 (L-form), 5-fluorouracil administered intravenously at a dose of 400 mg/m\^2 bolus followed by a 46-hour continuous infusion at a dose of 2,400 mg/m\^2) on Day 1 of 14 days treatment cycle until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. | 188 |
| Total | 289 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ongoing at data cut-off | 0 | 1 |
Baseline characteristics
| Characteristic | Cetuximab Plus FOLFIRI | Cetuximab Plus FOLFOX | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 31 Participants | 43 Participants | 74 Participants |
| Age, Categorical Between 18 and 65 years | 70 Participants | 145 Participants | 215 Participants |
| Sex: Female, Male Female | 35 Participants | 69 Participants | 104 Participants |
| Sex: Female, Male Male | 66 Participants | 119 Participants | 185 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 101 | 177 / 188 |
| serious Total, serious adverse events | 37 / 101 | 64 / 188 |
Outcome results
Primary
Percentage of Subjects With Best Overall Confirmed Response Rate (BORR)
Response rate was defined as the percentage of subjects with BORR (confirmed complete response \[CR\] or partial response \[PR\]) according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. As per RECIST v 1.0 criteria for target lesions and assessed by magnetic resonance imaging (MRI): CR = disappearance of all target lesions; PR = at least 30 percent (%) decrease in the sum of the longest diameter of target lesions. Response rate will be assessed every 8 weeks.
Time frame: From the start of the trial until disease progression, death or last tumor assessment, reported between day of first subject recruited until data cut-off date (31 May 2012)
Population: Intention-to-treat (ITT) population consisted of all the enrolled subjects who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus FOLFIRI | Percentage of Subjects With Best Overall Confirmed Response Rate (BORR) | 54.5 Percentage of subjects |
| Cetuximab Plus FOLFOX | Percentage of Subjects With Best Overall Confirmed Response Rate (BORR) | 61.2 Percentage of subjects |
95% CI: [0.8078, 2.1491]
Secondary
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death
An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From the start of the trial until disease progression, death or last tumor assessment, reported between day of first subject recruited and until data cut-off date (31 March 2014)
Population: Safety population consisted of all the enrolled subjects who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cetuximab Plus FOLFIRI | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs | 99 Subjects |
| Cetuximab Plus FOLFIRI | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | Treatment Emergent SAEs | 37 Subjects |
| Cetuximab Plus FOLFIRI | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs Leading to Death | 5 Subjects |
| Cetuximab Plus FOLFIRI | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs Leading to Discontinuation | 0 Subjects |
| Cetuximab Plus FOLFOX | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs Leading to Discontinuation | 0 Subjects |
| Cetuximab Plus FOLFOX | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs | 180 Subjects |
| Cetuximab Plus FOLFOX | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs Leading to Death | 10 Subjects |
| Cetuximab Plus FOLFOX | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), TEAEs Leading to Discontinuation and TEAEs Leading to Death | Treatment Emergent SAEs | 64 Subjects |
Secondary
Overall Survival (OS) Time
OS time was defined as the time from first administration of study drug until date of death, assessed up to 5 years. OS time was censored if the subject was found to be alive on the last date of the assessment.
Time frame: From the start of the trial until disease progression, death or last tumor assessment, reported between day of first subject recruited and until data cut-off date (31 March 2014)
Population: The ITT population consisted of all the enrolled subjects who received at least one dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFIRI | Overall Survival (OS) Time | 26.6 months |
| Cetuximab Plus FOLFOX | Overall Survival (OS) Time | 27.0 months |
Secondary
Progression-Free Survival (PFS) Time
PFS time was defined as the time from first administration of study drug until first observation of disease progression or death when death occurs within 90 days of the last tumor assessment or first study drug dose whichever occurred.
Time frame: From the start of the trial until disease progression, death or last tumor assessment, reported between day of first subject recruited and until data cut-off date (31 March 2014)
Population: The ITT population consisted of all the enrolled subjects who received at least one dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus FOLFIRI | Progression-Free Survival (PFS) Time | 11.1 months |
| Cetuximab Plus FOLFOX | Progression-Free Survival (PFS) Time | 11.1 months |