Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication ZALTRAP, in combination with fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. FDA label
Also known as AVE0005 (aflibercept), Aflibercept, Zaltrap
AVE0005 · 20 trials · 23 indications
Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during on-treatment period. On-treatment period was defined as the time from the first dose of treatment to 30 days after the last dose of treatment (either Aflibercept or FOLFIRI). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs.
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.
Overall Survival was the time interval from the date of randomization to the date of death due to any cause. Once disease progression was documented, participants were followed every 2 months for survival status, until death or until the study cutoff date, whichever came first. The final data cutoff date for the analysis of OS was the date when 863 deaths had occurred (07 February 2011). OS was estimated using the Kaplan-Meier method, and the Hazard Ratio was estimated using the Cox Proportional Hazard Model.
Overall survival (OS) time was measured as the time from date of randomization to the date of death due to any cause. The median OS time and its 95.6% confidence interval were estimated using the Kaplan-Meier method. In the absence of confirmation of death, the participant was censored at the last date he/she was known to be alive or the study cut-off date (when 873 deaths have occurred), whichever was earlier.
Assuming that the number of treatment successes (alive and progression-free) is binomially distributed, proportion estimates along with their corresponding exact 95% confidence intervals will be calculated.
The Pathologic Complete Response (pCR) Rate is defined as the number of pathologic complete responders among all patients evaluable for response, including evaluable patients who did not proceed to surgery. A pCR is defined as the absence of any residual abnormality detected in a pathological specimen.
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.
PFS rate at 12 months was defined as the percentage of patients alive without disease progression at 12 months after randomization. The primary efficacy analysis was based on assessment by the Independent Review Committee (IRC). The study was not powered for comparison of PFS rate at 12 months between the two arms (non-comparative, open-label study). Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.0), as at least a 20 percent increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions.
RPR was defined as at least a two-fold increase in the time to repeat paracentesis (TRP) as compared to the average duration of the 2 intervals between the 3 most recent paracenteses prior to study registration (ie, the baseline interval of paracentesis). Percentage of participants with a repeat paracentesis response were the number of participants with RPR / number of total participants \* 100.
TRP was defined as the number of days between the date of randomization and the date of the first post-randomization paracentesis. For participants who did not undergo a postrandomization paracentesis on study, TRP was calculated from randomization to the end of the double-blind treatment period.
OR included Complete Response (CR) and Partial Response (PR). Per RECIST, CR was disappearance of all target or non-target lesions, or normalization of tumor marker levels (for non-target lesions) and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with baseline sum LD as reference. Tumors were assessed by an independent third-party core imaging laboratory evaluating the chest, abdomen, and pelvis by Computerized Tomography (CT) scans or Magnetic Resonance Imaging (MRI) scans; and responses were confirmed by repeat tumor imaging 4-6 weeks later.
OR included Complete Response (CR) and Partial Response (PR). Per RECIST, CR was disappearance of all target or non-target lesions, or normalization of tumor marker levels (for non-target lesions) and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with baseline sum LD as reference. Tumors were assessed by an independent third-party core imaging laboratory evaluating the chest, abdomen, and pelvis by Computerized Tomography (CT) scans or Magnetic Resonance Imaging (MRI) scans; and responses were confirmed by repeat tumor imaging 4-6 weeks later.
OR was either complete response (CR) or partial response (PR) based on RECIST or modified RECIST. CR was the disappearance of all target/nor-target lesions; and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with reference to the baseline sum LD (According to modified RECIST, to calculate LD for cavitated lesions, the longest cavitation diameters were subtracted from the LD of cavitated target lesions). Assessments were made by the IRC, and confirmed by repeat tumor imaging 4-6 weeks after documentation of the initial response.
OR was either complete response (CR) or partial response (PR) based on RECIST or modified RECIST. CR was the disappearance of all target/nor-target lesions; and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with reference to the baseline sum LD (According to modified RECIST, to calculate LD for cavitated lesions, the longest cavitation diameters were subtracted from the LD of cavitated target lesions). Assessments were made by the Investigator, and confirmed by repeat tumor imaging 4-6 weeks after documentation of the initial response.
| Arm | Type | Description |
|---|---|---|
| Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin) | EXPERIMENTAL | Aflibercept 4 mg/kg intravenous (IV) infusion over 60 minutes followed by Irinotecan 180 mg/m\^2 IV infusion over 90 minutes and Leucovorin 400 mg/m\^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m\^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m\^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator's decision or participant's refusal of further treatment. |
| Placebo | PLACEBO_COMPARATOR | Placebo for aflibercept intravenous (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. |
| Aflibercept | EXPERIMENTAL | 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. |
| Placebo/FOLFIRI | PLACEBO_COMPARATOR | Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) starting on Day 1 of a 2-week cycle until a treatment discontinuation criterion was met |
| Aflibercept/FOLFIRI | EXPERIMENTAL | Participants with Metastatic Colorectal Cancer administered Aflibercept followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) starting on Day 1 of a 2-week cycle until a treatment discontinuation criterion was met |
| Aflibercept/Docetaxel | EXPERIMENTAL | Participants with Non-Small-Cell Lung Cancer (NSCLC) were administered Aflibercept immediately followed by Docetaxel every three weeks until disease progression, unacceptable toxicity, or participant's refusal. |
| Placebo/Docetaxel | PLACEBO_COMPARATOR | Participants with Non-Small-Cell Lung Cancer (NSCLC) were administered Placebo immediately followed by Docetaxel every three weeks until disease progression, unacceptable toxicity, or participant's refusal. |
| Aflibercept (combination chemotherapy) | EXPERIMENTAL | Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102). |
| FOLFOX6/Aflibercept/Radiation/Surgery | EXPERIMENTAL | Preoperative Chemoradiation: (6 weeks) * 5-FU: 225 mg/m2 per day by intravenous continuous infusion (IVCI), Days 1 thru 42; * Radiation: 50.4 Gy (1.8 Gy/day or 28 fractions) Mon thru Fri, Weeks 1 thru 6; * Aflibercept: 4 mg/ kg, via IV infusion, Days 1 and 15. Surgery at least 6 weeks after last day of aflibercept: Patients will undergo abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines. Postoperative Chemotherapy and Aflibercept Treatments (four 28-day cycles): * Aflibercept (administered first): 4 mg/kg IV for approximately 1 hour (no more than 2 hours) on Days 1 and 15 of each cycle. * Modified FOLFOX6: * Leucovorin: 400 mg/m2 as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * Oxaliplatin: 85 mg/m2 IV as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * 5-FU: 400-mg/m2 bolus for 2 to 4 minutes followed by 2400 mg/m2 for 46 hours on Days 1 and 15 of each cycle. |
| FOLFIRI-AFLIBERCEPT | EXPERIMENTAL | Aflibercept 4 mg/kg administered over 1 hour on Day 1, followed by FOLFIRI regimen. Treatment will be repeated every 2 weeks. FOLFIRI regimen: Irinotecan 180 mg/m² intravenous (IV) infusion and folinic acid 400 mg/m² IV infusion followed by: 5-fluorouracil (5-FU) 400 mg/m² IV bolus followed by: 5-FU 2400 mg/m² continuous IV infusion over 46 hours. FOLFIRI administration will immediately follow the aflibercept one. In the absence of PD after 6 months of the combination of chemotherapy and aflibercept, the patient will be treated with a maintenance therapy with aflibercept alone until PD or unacceptable toxicities, investigator's decision or patient's refusal of further treatment or death, whichever comes first. |
| Aflibercept + FOLFIRI | EXPERIMENTAL | Aflibercept 4 mg/kg intravenous (IV) infusion (1-2 hours) on Day 1 of Cycle 1 and every 2 weeks (q2w) thereafter, in combination with FOLFIRI regimen on Days 1-3 of Cycle 1 and q2w thereafter until disease progression (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. |
| mFOLFOX6 only | ACTIVE_COMPARATOR | modified FOLFOX6 chemotherapy regimen |
| mFOLFOX6 + aflibercept | EXPERIMENTAL | modified FOLFOX6 chemotherapy regimen in combination with aflibercept |
| Aflibercept 2.0 mg/kg | EXPERIMENTAL | Participants with advanced ovarian epithelial adenocarcinoma administered 2.0 mg/kg Aflibercept. |
| Aflibercept 4.0 mg/kg | EXPERIMENTAL | Participants with advanced ovarian epithelial adenocarcinoma administered 4.0 mg/kg Aflibercept. |
| Aflibercept/ docetaxel | EXPERIMENTAL | Patients with advanced cancer will receive different doses of aflibercept in combination with approved dose of docetaxel. Aflibercept 4 or 6mg/kg over 1 hour IV immediately followed by Docetaxel 75mg/m2 IV over 1 hour on Day 1, every 3 weeks |
| AVE0005 (aflibercept) | EXPERIMENTAL | - |
| 1 | EXPERIMENTAL | 4 mg/kg every 2 weeks |
| 2 | PLACEBO_COMPARATOR | matching placebo |
| Aflibercept RCHOP 14 | EXPERIMENTAL | Aflibercept (25 mg/ml by IV over an hour) in combination with fixed dose of rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) administered every 2 weeks. A dose of 2.0 mg/kg administered as Dose Level 1, 4.0 mg/kg as Dose Level 2, and 6.0 mg/kg dose as Dose level 3. |
| Aflibercept RCHOP 21 | EXPERIMENTAL | Aflibercept (25 mg/ml by IV over an hour) in combination with fixed dose of rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) administered every 3 weeks. A dose of 3.0 mg/kg administered as Dose Level 1, 6.0 mg/kg as Dose Level 2, and 8.0 mg/kg dose as Dose level 3. |
| aflibercept + docetaxel | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| AFLIBERCEPT | DRUG | Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous |
| Irinotecan | DRUG | Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous |
| Fluorouracil | DRUG | Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous |
| Leucovorin | DRUG | Pharmaceutical form:Concentrate for solution for infusion; Route of administration: Intravenous |
| Placebo | DRUG | Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous |
| Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®) | DRUG | 4 mg/kg of Aflibercept was administered IV over 1 hour on Day 1, every 2 weeks. |
| FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) | DRUG | The FOLFIRI regimen was initiated immediately after Placebo administration on Day 1 The FOLFIRI regimen included: * 180 mg/m² Irinotecan (Campto®, Camptosar®) IV infusion over 90 minutes and dl leucovorin 400 mg/m² (200 mg/m² for the l-isomer form) IV infusion over 2 hours, followed by: * 5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by: * 5-FU 2400 mg/m² continuous IV infusion over 46-hours |
| Docetaxel (Taxotere®) | DRUG | 75 mg/m² docetaxel in 250 mL dextrose 5% or NaCl 0.9% administered intravenously (IV) over 1 hour, on Day 1 every 3 weeks. |
| Dexamethasone (pre- and post-medication for docetaxel) | DRUG | As a pre- and post-medication for docetaxel, 8 mg dexamethasone was administered orally, the evening before Day 1, on Day 1 (early morning, 1 hour before docetaxel treatment, and evening) and on Day 2 (morning and evening). |
| Placebo (for aflibercept) | DRUG | Sterile aqueous buffered solution identical to aflibercept 1-hour IV on Day 1 of each 3-Week cycle |
| Docetaxel | DRUG | Marketed formulation 75 mg/m², 1 hour IV on Day 1 of each 3-week cycle (immediately after Aflibercept or placebo) |
| Prednisone or Prednisolone | DRUG | Marketed formulation 5 mg twice daily PO from day 1 continuously |
| oxaliplatin | DRUG | 85 mg/m2 IV infused over 2 hours |
| Correlative Studies | OTHER | Patients are required to have tissue available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center. |
| DCE MRI | PROCEDURE | Images at weeks 0, and after 8 weeks +/- 1 week of treatment (after Cycle 2). |
| f18FDG-PET | RADIATION | 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG). FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers, including colorectal cancer (99-102). |
| PET (positron emission tomography) | PROCEDURE | Correlative studies |
| Radiation | RADIATION | - |
| Surgery | PROCEDURE | Abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines |
| FOLFOX6 | DRUG | - |
| 5-Fluorouracil | DRUG | - |
| Folinic Acid | DRUG | - |
| Levofolinate | DRUG | Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous |
| 5-FU | DRUG | Pharmaceutical form: Solution for infusion (marketed formulation); Route of administration: Intravenous |
| Aflibercept (AVE0005) | DRUG | Pharmaceutical form: solution for infusion Route of administration: intravenous |
| Docetaxel (XRP6976) | DRUG | Pharmaceutical form: solution for infusion Route of administration: intravenous |
| AVE0005 (aflibercept) | DRUG | IV infusion |
| S-1 | DRUG | oral administration |
Inclusion criteria: * Histologically or cytologically proven adenocarcinoma of the colon or rectum. * Metastatic disease. * Age ≥18 years. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. * One and only one prior chemotherapeutic regimen for metastatic disease. This prior ch...
AVE0005 was studied for colorectal neoplasms, specifically metastatic colorectal cancer. The single trial of AVE0005 combined it with FOLFIRI chemotherapy in Japanese patients with metastatic colorectal cancer. It is an investigational agent and is not an approved treatment for colorectal cancer.
AVE0005 is developed by Sanofi, which trades under the ticker SNY. Sanofi sponsored the clinical trial of AVE0005 in metastatic colorectal cancer. The asset is an oncology program within Sanofi's pipeline.
AVE0005 is in Phase 1 clinical development. Its only recorded trial, NCT00921661, was a Phase 1 study, and that trial is now completed. AVE0005 is investigational and has not been approved for any indication.
AVE0005 has been evaluated in one clinical trial, NCT00921661, titled Study of Intravenous Aflibercept in Combination With FOLFIRI in Japanese Patients With Metastatic Colorectal Cancer. That Phase 1 trial enrolled 16 patients in Japan and is completed. No trials of AVE0005 are currently active.
AVE0005 is also known as AVE0005 (aflibercept). The name AVE0005 refers to the same agent studied under the aflibercept designation in the metastatic colorectal cancer trial NCT00921661. Readers searching for either name are looking at the same Sanofi asset.
AVE0005 was tested in a single Phase 1 trial, NCT00921661, in Japanese patients with metastatic colorectal cancer. The study combined intravenous AVE0005 with FOLFIRI, enrolled 16 patients aged 20 years and older, was uncontrolled, and did not use randomization or double blinding. It is completed.