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Mechanism of Action
Ziv-aflibercept acts as a soluble receptor that binds to human VEGF-A (equilibrium dissociation constant KD of 0.5 pM for VEGF-A165 and 0.36 pM for VEGF-A121), to human VEGF-B (KD of 1.92 pM), and to human PlGF (KD of 39 pM for PlGF-2). By binding to these endogenous ligands, ziv-aflibercept can inhibit the binding and activation of their cognate receptors. This inhibition can result in decreased neovascularization and decreased vascular permeability.
In animals, ziv-aflibercept was shown to inhibit the proliferation of endothelial cells, thereby inhibiting the growth of new blood vessels. Ziv-aflibercept inhibited the growth of xenotransplanted colon tumors in mice.
Plasma concentrations of free and VEGF-bound ziv-aflibercept were measured using specific enzyme-linked immunosorbent assays (ELISAs). Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetics in the dose range of 2-9 mg/kg. Following 4 mg/kg every two weeks intravenous administration of ZALTRAP, the elimination half-life of free ziv-aflibercept was approximately 6 days (range 4-7 days). Steady state concentrations of free ziv-aflibercept were reached by the second dose. The accumulation ratio for free ziv-aflibercept was approximately 1.2 after administration of 4 mg/kg every two weeks.
Based on a population pharmacokinetic analysis, age, race, and gender did not have a clinically important effect on the exposure of free ziv-aflibercept. Patients weighing ≥ 100 kg had a 29% increase in systemic exposure compared to patients weighing 50 to 100 kg.
Based on a population pharmacokinetic analysis which included patients with mild (total bilirubin > 1.0x-1.5x ULN and any SGOT/AST, n=63) and moderate (total bilirubin > 1.5x-3x ULN and any SGOT/AST, n=5) hepatic impairment, there was no effect of total bilirubin, aspartate amino transferase, and alanine amino transferase on the clearance of free ziv-aflibercept. There is no data available for patients with severe hepatic impairment (total bilirubin > 3x ULN and any SGOT/AST).
Based on a population pharmacokinetic analysis which included patients with mild (CLCR 50-80 mL/min, n=549), moderate (CLCR 30-50 mL/min, n=96), and severe renal impairment (CLCR < 30 mL/min, n=5), there was no clinically important effect of creatinine clearance on the clearance of free ziv-aflibercept.
The effect of 6 mg/kg intravenous ZALTRAP every three weeks on QTc interval was evaluated in 87 patients with solid tumors in a randomized, placebo-controlled study. No large changes in the mean QT interval from baseline (i.e., greater than 20 ms as corrected for placebo) based on
Fridericia correction method were detected in the study. However, a small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded due to limitations of the study design.
Animal Toxicology and/or Pharmacology
Weekly/every two weeks intravenous administration of ziv-aflibercept to growing young adult (sexually mature) cynomolgus monkeys for up to 6 months resulted in changes in the bone (effects on growth plate and the axial and appendicular skeleton), nasal cavity (atrophy/loss of the septum and/or turbinates), kidney (glomerulopathy with inflammation), ovary (decreased number of maturing follicles, granulosa cells, and/or theca cells), and adrenal gland (decreased vacuolation with inflammation). Most ziv-aflibercept-related findings were noted from the lowest dose tested (3 mg per kg per dose) correlating to 60% of the AUC at the human recommended dose.
In another study in sexually immature cynomolgus monkeys (treated intravenous for 3 months), similar effects were observed. The skeletal and nasal cavity effects were not reversible after a post-dosing recovery period.
Repeated administration of ziv-aflibercept resulted in a delay in wound healing in rabbits. In full-thickness excisional and incisional skin wound models, ziv-aflibercept administration reduced fibrous response, neovascularization, epidermal hyperplasia/re-epithelialization, and tensile strength.
Study 1 was a randomized, double-blind, placebo-controlled study in patients with metastatic colorectal cancer (mCRC) who are resistant to or have progressed during or within 6 months of receiving oxaliplatin-based combination chemotherapy, with or without prior bevacizumab. A total of 1226 patients were randomized (1:1) to receive either ZALTRAP (N=612; 4 mg per kg as a 1 hour intravenous infusion on day 1) or placebo (N=614), in combination with 5-fluorouracil plus irinotecan [FOLFIRI: irinotecan 180 mg per m²IV infusion over 90 minutes and leucovorin (dl racemic) 400 mg per mē intravenous infusion over 2 hours at the same time on day 1 using a Y-line, followed by 5-FU 400 mg per mē intravenous bolus, followed by 5-FU 2400 mg per mē continuous intravenous infusion over 46-hours]. The treatment cycles on both arms were repeated every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall survival. Treatment assignment was stratified by the ECOG performance status (0 versus 1 versus 2) and according to prior therapy with bevacizumab (yes or no).
Demographics characteristics were similar between treatment arms. Of the 1226 patients randomized, the median age was 61 years, 59% were men, 87% were White, 7% were Asian, 3.5% were Black, and 98% had a baseline ECOG performance status (PS) of 0 or 1. Among the 1226 randomized patients, 89% and 90% of patients treated with placebo/FOLFIRI and ZALTRAP/FOLFIRI, respectively, received prior oxaliplatin-based combination chemotherapy in the metastatic/advanced setting. A total of 346 patients (28%) received bevacizumab in combination with the prior oxaliplatin-based treatment.
Overall efficacy results for the ZALTRAP/FOLFIRI regimen versus the placebo/FOLFIRI regimen are summarized in Figure 1 and Table 2.
Figure 1 : Overall survival (months) – Kaplan-Meier
curves by treatment group
Table 2 : Main efficacy
|Number of deaths, n (%)||460 (74.9%)||403 (65.8%)|
|Median overall survival (95% CI) (months)||12.06 (11.07 to 13.08)||13.50 (12.52 to 14.95)|
|Stratified Hazard ratio (95% CI)||0.817 (0.714 to 0.935)|
|Stratified Log-Rank test p-value||0.0032|
|Progression Free Survival (PFS)a|
|Number of events, n (%)||454 (73.9%)||393 (64.2%)|
|Median PFS (95% CI) (months)||4.67 (4.21 to 5.36)||6.90 (6.51 to 7.20)|
|Stratified Hazard ratio (95% CI)||0.758 (0.661 to 0.869)|
|Stratified Log-Rank test p-value b||0.00007|
|Overall Response Rate (CR+PR) (95% CI) (%)c||11.1 (8.5 to 13.8)||19.8 (16.4 to 23.2)|
|Stratified Cochran-Mantel-Haenszel test p-value||0.0001|
|aPFS (based on tumor assessment by the IRC): Significance
threshold is set to 0.0001.
bStratified on ECOG Performance Status (0 vs 1 vs 2) and Prior Bevacizumab (yes vs no)
cOverall objective response rate by IRC
Planned subgroup analyses for overall survival based on stratification factors at randomization yielded an HR of 0.86 (95% CI: 0.68 to 1.1) in patients who received prior bevacizumab and an HR of 0.79 (95% CI: 0.67 to 0.93) in patients without prior bevacizumab exposure.
Last reviewed on RxList: 11/18/2013
This monograph has been modified to include the generic and brand name in many instances.
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