Colorectal Cancer Metastatic
Conditions
Brief summary
Primary Objective: To evaluate the improvement in progression-free survival (PFS) of aflibercept versus placebo in participants with metastatic colorectal cancer treated with FOLFIRI as second-line treatment for metastatic disease. Secondary Objectives: To compare the overall survival (OS) in the 2 treatment arms. To compare the overall response rate (ORR) in the 2 treatment arms. To assess the safety profile of the 2 treatment arms. To assess immunogenicity of intravenous (IV) aflibercept in selected centers.
Detailed description
Screening occurred from signed informed consent to randomization (up to 21 days). A treatment cycle was defined as a 2 week-period. All participants were followed during the study treatment and follow-up period until death or study cut off date, which ever comes first.
Interventions
DRUGAflibercept
Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous
DRUGPlacebo
Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological or cytological proven adenocarcinoma of the colon or rectum. * Metastatic disease that was not amenable to potentially curative treatment. * One and only one prior chemotherapeutic regimen for metastatic disease. This prior chemotherapy must be an oxaliplatin containing regimen. Participants who were relapsed within 6 months of completion of oxaliplatin based adjuvant chemotherapy were eligible.
Exclusion criteria
* Prior therapy with irinotecan. * Eastern Cooperative Oncology Group (ECOG) performance status \>1. * Less than 28 days elapsed from prior radiotherapy, from prior surgery and prior chemotherapy to the time of randomization. Less than 42 days elapsed from prior major surgery to the time to randomization. * Adverse events (with exception of alopecia, peripheral sensory neuropathy grade ≤ 2 and those listed in specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | 26.7 months | PFS was defined as the time interval from the date of randomization to the date of first observation of either tumor progression or death due to any cause. Tumor assessment was performed by Independent Review Committee (IRC) as per response evaluation criteria in solid tumors (RECIST) version 1.0. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 31.6 months | OS was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the earliest between the last date of the participants was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method. |
| Percentage of Participants With Objective Response | 26.6 months | Objective response rate was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR), as assessed by Investigators and the IRC according to RECIST 1.0 criteria, relative to the total number of participants in the relevant analysis population. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions. |
Countries
China, Hong Kong, Japan, Singapore, Taiwan
Participant flow
Recruitment details
The study was conducted at 37 centers in 5 countries. A total of 332 participants were randomized between 17 July 2012 and 18 March 2014.
Pre-assignment details
Due to treatment kit misallocation, part of the patients randomized to placebo received aflibercept for 1/several treatment cycles and are presented as a separate group for safety evaluation. EOT criteria were: disease progression/death, un-tolerable toxicity, consent withdrawal/Investigator decision.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo for IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m\^2 IV infusion and leucovorin 400 mg/m\^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m\^2 followed by continuous IV infusion 2400 mg/m\^2. | 109 |
| Aflibercept Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m\^2 IV infusion and leucovorin 400 mg/m\^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m\^2 followed by continuous IV infusion 2400 mg/m\^2. | 223 |
| Total | 332 |
Baseline characteristics
| Characteristic | Placebo | Aflibercept | Total |
|---|---|---|---|
| Age, Continuous | 53.0 years STANDARD_DEVIATION 11.3 | 55.1 years STANDARD_DEVIATION 10.9 | 54.4 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 46 Participants | 95 Participants | 141 Participants |
| Sex: Female, Male Male | 63 Participants | 128 Participants | 191 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 33 | 109 / 111 | 188 / 188 |
| serious Total, serious adverse events | 9 / 33 | 30 / 111 | 43 / 188 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS was defined as the time interval from the date of randomization to the date of first observation of either tumor progression or death due to any cause. Tumor assessment was performed by Independent Review Committee (IRC) as per response evaluation criteria in solid tumors (RECIST) version 1.0. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates.
Time frame: 26.7 months
Population: Intent-to-Treat (ITT) population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Progression-free Survival (PFS) | 5.59 months |
| Aflibercept | Progression-free Survival (PFS) | 6.93 months |
Secondary
Overall Survival (OS)
OS was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the earliest between the last date of the participants was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method.
Time frame: 31.6 months
Population: ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival (OS) | 11.93 months |
| Aflibercept | Overall Survival (OS) | 14.59 months |
Secondary
Percentage of Participants With Objective Response
Objective response rate was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR), as assessed by Investigators and the IRC according to RECIST 1.0 criteria, relative to the total number of participants in the relevant analysis population. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.
Time frame: 26.6 months
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Objective Response | 3.7 percentage of participants |
| Aflibercept | Percentage of Participants With Objective Response | 18.4 percentage of participants |