Colorectal Cancer Metastatic
Conditions
Brief summary
Primary Objective: To assess efficacy aflibercept + 5-fluorouracil (5-FU)/levofolinate/irinotecan (FOLFIRI) by objective response rate (ORR). Secondary Objective: To assess the following: * safety profile; * progression free survival (PFS); * overall survival (OS); * pharmacokinetics (PK); * immunogenicity.
Detailed description
Screening was up to 24 days. Treatment period was continued until DP, unacceptable toxicity, or participant's refusal. Follow up period was continued until death, participant's refusal, or end of study, whichever came first. This trial was conducted in Japan, where the International Nonproprietary Name (INN) designation for the study molecule is aflibercept and this term is therefore used throughout the synopsis. In the US, the US proper name is ziv-aflibercept.
Interventions
DRUGAflibercept
Pharmaceutical form: Concentrated solution (100 mg/4 mL \[25 mg/mL\], 200 mg/8 mL \[25 mg/mL\]) for infusion; Route of administration: Intravenous
DRUGLevofolinate
Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous
DRUGIrinotecan
Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous
DRUG5-FU
Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically proven adenocarcinoma of the colon or rectum. * Metastatic disease that was not amenable to potentially curative treatment. * Participants with measurable disease. * One prior chemotherapeutic regimen (containing oxaliplatin) for metastatic disease. * Participants who relapsed within 6 months of completion of oxaliplatin-based adjuvant chemotherapy were also eligible.
Exclusion criteria
* Prior therapy with irinotecan. * Less than 28 days elapsed from prior radiotherapy, prior surgery, or prior chemotherapy to the time of registration. * Unresolved toxicity (grade \>1) from prior anticancer therapy. * Eastern Cooperative Oncology Group (ECOG) performance status \>1. * Brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis. * Other prior malignancy. * Pregnant or breast-feeding women. * Uncontrolled hypertension. * Inadequate bone marrow function, liver function, or renal function. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Response | Baseline and every 6 weeks until DP (maximum duration: 16.4 months) | Overall response in participants was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) assessed by an independent radiological review committee (IRRC) according to response evaluation criteria in solid tumors (RECIST) version 1.1. CR was defined as disappearance of all target lesions; any lymph node (target or non-target) must have reduction in the short axis to \<10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Percentage of participants with overall response and the 95% confidence interval (CI) were provided. The 95% CI was calculated using normal approximation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Baseline up to death or study cut--off (maximum duration: 24.7 months) | OS was defined as the time interval from the date of first study drug administration to the date of death due to any cause. If death was not observed, the participant was censored at the last date the participant was known to be alive or the study cut-off date, whichever was first. OS was estimated by Kaplan-Meier estimates. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | First dose (Day 1 of Cycle 1) of study treatment up to end of treatment visit (30 days after last dose of study treatment) (maximum duration: 77 weeks) | Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on--treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment. |
| Aflibercept Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay | Baseline, at any time post baseline and 90 days after the last dose of aflibercept | Blood samples of participants were analyzed by using a titer-based, bridging immunoassay developed and validated to detect aflibercept ADA in human serum. Samples with positive antibody levels were further analyzed using a validated, non-quantitative, competitive ligand binding assay to detect NAb. |
| Maximum Observed Plasma Concentration (Cmax) for Free and Vascular Endothelial Growth Factor (VEGF)-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1. |
| Maximum Observed Plasma Concentration (Cmax) for Free Aflibercept: ITT Population | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed pharmacokinetic (PK) analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants. |
| Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free Aflibercept: ITT Population | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants. |
| Area Under the Concentration Time Curve (AUC) for Free Aflibercept: ITT Population | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants. |
| Total Body Clearance (CL) for Free Aflibercept: ITT Population | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants. |
| Volume of Distribution at the Steady State (Vss) for Free Aflibercept: ITT Population | Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling | Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants. |
| Time to Reach Maximum Plasma Concentration Observed (Tmax) for Free and VEGF-Bound Aflibercept in Cycle 1: Participants With Additional Blood Sampling for Detailed PK Analysis | Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1. |
| Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1. |
| Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1. |
| Progression Free Survival (PFS) | Baseline and every 6 weeks until DP or death, due to any cause (maximum duration: 16.4 months) | PFS was defined as the time interval from the date of first study drug administration to the date of first observation of DP or death due to any cause, whichever came first. If death or progression was not observed, the participant was censored at the date of participant's last valid progression-free tumor assessment prior to the study cut-off date. DP for PFS was assessed by the IRRC based on tumor imaging according to RECIST 1.1. Progression in disease was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study with absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was estimated by Kaplan-Meier estimates. |
| Total Body Clearance (CL) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1. |
| Volume of Distribution at the Steady State (Vss) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1. |
| Terminal Elimination Half-life (t1/2z) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1. |
| Steady State Drug Concentration (Css) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 2.5, 21 and 45 hours post 5-FU infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of 5-FU in combination with aflibercept and irinotecan in Cycle 1. |
| Clearance at Steady State (CLss) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 2.5, 21 and 45 hours post 5-FU infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of 5-FU in combination with aflibercept and irinotecan in Cycle 1. |
| Maximum Observed Plasma Concentration (Cmax) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Predose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1. |
| Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1. |
| Area Under the Concentration Time Curve (AUC) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1. |
| Terminal Elimination Half-life (t1/2z) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1. |
| Active Metabolite SN-38 / Irinotecan Ratio on Area Under the Concentration Time Curve (Rmet): Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non - compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1. |
| Total Body Clearance (CL) for Irinotecan: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan in combination with aflibercept and 5-FU in Cycle 1. |
| Volume of Distribution at the Steady State (Vss) for Irinotecan: Participants With Additional Blood Sampling for Detailed PK Analysis | Predose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan in combination with aflibercept and 5-FU in Cycle 1. |
| Area Under the Concentration Time Curve (AUC) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1 | In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1. |
Countries
Japan
Participant flow
Recruitment details
The study was conducted at 19 sites in Japan. A total of 68 participants were screened between 30 July 2013 and 12 March 2014, out of which 62 were enrolled and treated.
Pre-assignment details
Among 68 participants screened, 6 were screen failures due to elevated urine protein-creatinine ratio (UPCR) and inadequate liver function tests (LFTs).
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept + FOLFIRI Aflibercept 4 mg/kg IV infusion (1-2 hours) on Day 1 of Cycle 1 and q2w thereafter, in combination with FOLFIRI regimen on Days 1-3 of Cycle 1 and q2w thereafter until DP, unacceptable toxicity or participant's refusal. FOLFIRI regimen: IV infusions of levofolinate 200 mg/m\^2 (2 hours) and irinotecan 180 mg/m\^2 (90 minutes) simultaneously, followed by 5-FU 400 mg/m\^2 IV bolus injection followed by continuous IV infusion of 5-FU (46 hours) at 2400 mg/m\^2. | 60 |
| Total | 60 |
Baseline characteristics
| Characteristic | Aflibercept + FOLFIRI |
|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 9.8 |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 | 40 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 | 20 participants |
| Prior Treatment with Bevacizumab Did Not Have Prior Treatment | 10 participants |
| Prior Treatment with Bevacizumab Had Prior Treatment | 50 participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 62 / 62 |
| serious Total, serious adverse events | 20 / 62 |
Outcome results
Primary
Percentage of Participants With Overall Response
Overall response in participants was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) assessed by an independent radiological review committee (IRRC) according to response evaluation criteria in solid tumors (RECIST) version 1.1. CR was defined as disappearance of all target lesions; any lymph node (target or non-target) must have reduction in the short axis to \<10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Percentage of participants with overall response and the 95% confidence interval (CI) were provided. The 95% CI was calculated using normal approximation.
Time frame: Baseline and every 6 weeks until DP (maximum duration: 16.4 months)
Population: EP population: all registered participants with measurable disease at study entry \& with at least 1 valid post-baseline tumor evaluation. Participants who died due to DP or had documented radiological progressive disease before first post-baseline imaging evaluation were also included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept + FOLFIRI | Percentage of Participants With Overall Response | 8.3 percentage of participants |
Secondary
Active Metabolite SN-38 / Irinotecan Ratio on Area Under the Concentration Time Curve (Rmet): Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non - compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis. Here 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Active Metabolite SN-38 / Irinotecan Ratio on Area Under the Concentration Time Curve (Rmet): Participants With Additional Blood Sampling for Detailed PK Analysis | 0.0313 ratio | Standard Deviation 0.0133 |
Secondary
Aflibercept Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay
Blood samples of participants were analyzed by using a titer-based, bridging immunoassay developed and validated to detect aflibercept ADA in human serum. Samples with positive antibody levels were further analyzed using a validated, non-quantitative, competitive ligand binding assay to detect NAb.
Time frame: Baseline, at any time post baseline and 90 days after the last dose of aflibercept
Population: The safety population (AT population) included all registered participants who received at least 1 (even if incomplete) infusion of study treatment. Here 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aflibercept + FOLFIRI | Aflibercept Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay | At baseline in the ADA assay (n=62) | 1 participants |
| Aflibercept + FOLFIRI | Aflibercept Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay | At any time post-baseline in the ADA assay (n=62) | 0 participants |
| Aflibercept + FOLFIRI | Aflibercept Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay | At any time post-baseline in the NAb assay (n=62) | 0 participants |
| Aflibercept + FOLFIRI | Aflibercept Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay | At 90 days after last dose in the ADA assay (n=50) | 0 participants |
| Aflibercept + FOLFIRI | Aflibercept Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay | At 90 days after last dose in NAb assay (n=50) | 0 participants |
Secondary
Area Under the Concentration Time Curve (AUC) for Free Aflibercept: ITT Population
Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants.
Time frame: Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling
Population: ITT population included all registered participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve (AUC) for Free Aflibercept: ITT Population | 304.6 mcg*day/mL | Standard Deviation 62.8 |
Secondary
Area Under the Concentration Time Curve (AUC) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve (AUC) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 355 mcg*day/mL | Standard Deviation 61.5 |
Secondary
Area Under the Concentration Time Curve (AUC) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis. Here 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve (AUC) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma Irinotecan (n=10) | 17700 ng*h/mL | Standard Deviation 6400 |
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve (AUC) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma SN-38 (n=4) | 341 ng*h/mL | Standard Deviation 72.4 |
Secondary
Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free Aflibercept: ITT Population
Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants.
Time frame: Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling
Population: ITT population included all registered participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free Aflibercept: ITT Population | 246.9 mcg*day/mL | Standard Deviation 41.1 |
Secondary
Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1.
Time frame: Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis. Here 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma Free-Aflibercept (n=10) | 312 mcg*day/mL | Standard Deviation 51.8 |
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve From Time 0 to 14 Days Post Start of Infusion (AUC0-14 Day) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma VEGF-Bound Aflibercept (n=5) | 23.3 mcg*day/mL | Standard Deviation 2.45 |
Secondary
Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1.
Time frame: Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis. Here 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma Free-Aflibercept (n=10) | 321 mcg*day/mL | Standard Deviation 58.9 |
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Free and VEGF-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma VEGF-Bound Aflibercept (n=8) | 24.4 mcg*day/mL | Standard Deviation 6.17 |
Secondary
Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma Irinotecan | 16900 ng*h/mL | Standard Deviation 5970 |
| Aflibercept + FOLFIRI | Area Under the Concentration Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma SN-38 | 344 ng*h/mL | Standard Deviation 173 |
Secondary
Clearance at Steady State (CLss) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of 5-FU in combination with aflibercept and irinotecan in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 2.5, 21 and 45 hours post 5-FU infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Clearance at Steady State (CLss) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis | 122 liter/hour | Standard Deviation 76.2 |
Secondary
Maximum Observed Plasma Concentration (Cmax) for Free Aflibercept: ITT Population
Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed pharmacokinetic (PK) analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants.
Time frame: Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling
Population: Intent-to-Treat (ITT) population included all registered participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Maximum Observed Plasma Concentration (Cmax) for Free Aflibercept: ITT Population | 73.19 mcg/mL | Standard Deviation 10.72 |
Secondary
Maximum Observed Plasma Concentration (Cmax) for Free and Vascular Endothelial Growth Factor (VEGF)-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1.
Time frame: Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis. Here 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept + FOLFIRI | Maximum Observed Plasma Concentration (Cmax) for Free and Vascular Endothelial Growth Factor (VEGF)-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma Free-Aflibercept (n=10) | 90.8 mcg/mL | Standard Deviation 16.5 |
| Aflibercept + FOLFIRI | Maximum Observed Plasma Concentration (Cmax) for Free and Vascular Endothelial Growth Factor (VEGF)-Bound Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma VEGF-Bound Aflibercept (n=8) | 2.83 mcg/mL | Standard Deviation 0.836 |
Secondary
Maximum Observed Plasma Concentration (Cmax) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1.
Time frame: Predose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept + FOLFIRI | Maximum Observed Plasma Concentration (Cmax) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma Irinotecan | 2220 ng/mL | Standard Deviation 528 |
| Aflibercept + FOLFIRI | Maximum Observed Plasma Concentration (Cmax) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma SN-38 | 32.2 ng/mL | Standard Deviation 11.4 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on--treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
Time frame: First dose (Day 1 of Cycle 1) of study treatment up to end of treatment visit (30 days after last dose of study treatment) (maximum duration: 77 weeks)
Population: The safety population (AT population) included all registered participants who received at least 1 (even if incomplete) infusion of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept + FOLFIRI | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 62 participants |
Secondary
Overall Survival (OS)
OS was defined as the time interval from the date of first study drug administration to the date of death due to any cause. If death was not observed, the participant was censored at the last date the participant was known to be alive or the study cut-off date, whichever was first. OS was estimated by Kaplan-Meier estimates.
Time frame: Baseline up to death or study cut--off (maximum duration: 24.7 months)
Population: The safety population (AT population) included all registered participants who received at least 1 (even if incomplete) infusion of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aflibercept + FOLFIRI | Overall Survival (OS) | 15.59 months |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time interval from the date of first study drug administration to the date of first observation of DP or death due to any cause, whichever came first. If death or progression was not observed, the participant was censored at the date of participant's last valid progression-free tumor assessment prior to the study cut-off date. DP for PFS was assessed by the IRRC based on tumor imaging according to RECIST 1.1. Progression in disease was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study with absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was estimated by Kaplan-Meier estimates.
Time frame: Baseline and every 6 weeks until DP or death, due to any cause (maximum duration: 16.4 months)
Population: The safety population (all treated \[AT\] population) included all registered participants who received at least 1 (even if incomplete) infusion of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aflibercept + FOLFIRI | Progression Free Survival (PFS) | 5.42 months |
Secondary
Steady State Drug Concentration (Css) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of 5-FU in combination with aflibercept and irinotecan in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 2.5, 21 and 45 hours post 5-FU infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Steady State Drug Concentration (Css) for 5-FU: Participants With Additional Blood Sampling for Detailed PK Analysis | 930 ng/mL | Standard Deviation 461 |
Secondary
Terminal Elimination Half-life (t1/2z) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Terminal Elimination Half-life (t1/2z) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 4.47 days | Standard Deviation 0.68 |
Secondary
Terminal Elimination Half-life (t1/2z) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan and SN-38 in combination with aflibercept and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis. Here 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept + FOLFIRI | Terminal Elimination Half-life (t1/2z) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma Irinotecan (n=10) | 5.19 hours | Standard Deviation 0.736 |
| Aflibercept + FOLFIRI | Terminal Elimination Half-life (t1/2z) for Irinotecan and Its Active Metabolite SN-38: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma SN-38 (n=5) | 10.3 hours | Standard Deviation 3.08 |
Secondary
Time to Reach Maximum Plasma Concentration Observed (Tmax) for Free and VEGF-Bound Aflibercept in Cycle 1: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free and VEGF-bound aflibercept in combination with irinotecan and 5-FU in Cycle 1.
Time frame: Predose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis. Here 'n' signifies number of participants with available data for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aflibercept + FOLFIRI | Time to Reach Maximum Plasma Concentration Observed (Tmax) for Free and VEGF-Bound Aflibercept in Cycle 1: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma Free-Aflibercept (n=10) | 0.07 days |
| Aflibercept + FOLFIRI | Time to Reach Maximum Plasma Concentration Observed (Tmax) for Free and VEGF-Bound Aflibercept in Cycle 1: Participants With Additional Blood Sampling for Detailed PK Analysis | Plasma VEGF-Bound Aflibercept (n=8) | 13.97 days |
Secondary
Total Body Clearance (CL) for Free Aflibercept: ITT Population
Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants.
Time frame: Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling
Population: ITT population included all registered participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Total Body Clearance (CL) for Free Aflibercept: ITT Population | 0.8053 liter/day | Standard Deviation 0.1784 |
Secondary
Total Body Clearance (CL) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Total Body Clearance (CL) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 0.716 liter/day | Standard Deviation 0.204 |
Secondary
Total Body Clearance (CL) for Irinotecan: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan in combination with aflibercept and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Total Body Clearance (CL) for Irinotecan: Participants With Additional Blood Sampling for Detailed PK Analysis | 18.3 liter/hour | Standard Deviation 6.04 |
Secondary
Volume of Distribution at the Steady State (Vss) for Free Aflibercept: ITT Population
Sparse blood sampling was performed on 52 participants and additional blood sampling for detailed PK analysis was performed on 10 participants as per protocol. A population PK analysis was performed and an overall data is reported for all the participants.
Time frame: Pre-dose, 1, 4, 24, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with sparse sampling & pre-dose, 1, 2, 4, 8, 24, 48, 168, 336 hours post aflibercept infusion on Day 1 of Cycle 1 for participants with additional sampling
Population: ITT population included all registered participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Volume of Distribution at the Steady State (Vss) for Free Aflibercept: ITT Population | 6.197 liters | Standard Deviation 1.106 |
Secondary
Volume of Distribution at the Steady State (Vss) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of free aflibercept in combination with irinotecan and 5-FU in Cycle 1.
Time frame: Pre-dose (prior to aflibercept infusion), 1, 2, 4, 8, 24, 48, 168 and 336 hours post aflibercept infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Volume of Distribution at the Steady State (Vss) for Free Aflibercept: Participants With Additional Blood Sampling for Detailed PK Analysis | 3.53 liters | Standard Deviation 1.11 |
Secondary
Volume of Distribution at the Steady State (Vss) for Irinotecan: Participants With Additional Blood Sampling for Detailed PK Analysis
In 10 participants of ITT population, additional blood samples were obtained for detailed non-compartmental PK analysis of irinotecan in combination with aflibercept and 5-FU in Cycle 1.
Time frame: Predose (prior to aflibercept infusion), 1.5, 2, 4.5 and 23 hours post irinotecan infusion on Day 1 of Cycle 1
Population: Subset of ITT population with additional blood sampling for detailed non-compartmental PK analysis. Number of participants analyzed=participants with PK assessment for the subset analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept + FOLFIRI | Volume of Distribution at the Steady State (Vss) for Irinotecan: Participants With Additional Blood Sampling for Detailed PK Analysis | 92.5 liter | Standard Deviation 33.8 |