Pharmacological Class:
Fusion protein.

Active Ingredient(s):
Ziv-aflibercept 25mg/mL; soln for IV infusion after dilution; preservative-free.

Indication(s):
In combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Pharmacology:
Ziv-aflibercept is a recombinant fusion protein consisting of Vascular Endothelial Growth Factor (VEGF)-binding portions from the extracellular domains of human VEGF Receptors 1 and 2 fused to the Fc portion of the human IgG1. 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.

Clinical Trials:
Study 1 was a randomized, double-blind, placebo-controlled study in patients with 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 1,226 patients were randomized (1:1) to receive either Zaltrap (N=612; 4mg/kg as a 1 hour IV infusion on day 1) or placebo (N=614), in combination with 5-fluorouracil plus irinotecan [FOLFIRI: irinotecan 180mg/m2 IV infusion over 90 minutes and leucovorin (dl racemic) 400mg/m2 IV infusion over 2 hours at the same time on day 1 using a Y-line, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 2400mg/m2 continuous IV infusion over 46 hours]. The treatment cycles on both arms were repeated every 2 weeks until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall survival. Treatment assignment was stratified by the ECOG performance status (0 vs. 1 vs. 2) and according to prior therapy with bevacizumab (yes or no). Results showed that in patients previously treated with an oxaliplatin-containing regimen, adding Zaltrap to FOLFIRI significantly improved median overall survival from 12.06 months to 13.50 months (HR=0.817, 95% CI 0.714– 0.935; p= 0.0032), an 18% relative risk reduction.

Legal Classification:
Rx

Adults:
Start ziv-aflibercept prior to any component of the FOLFIRI regimen on treatment day. Give 4mg/kg as an IV infusion over 1 hour every 2 weeks; continue until disease progression or unacceptable toxicity. For recurrent or severe hypertension, suspend until controlled. Upon resumption, permanently reduce to 2mg/kg. For recurrent proteinuria, suspend until proteinuria <2grams per 24 hours, then permanently reduce to 2mg/kg.

Children:
Not established.

Warnings/Precautions:
Increased risk of hemorrhage; monitor for signs/symptoms. Do not start in patients with severe hemorrhage; discontinue if develops. Monitor for GI perforation, fistula formation, compromised wound healing; discontinue if occurs. Suspend therapy at least 4 weeks prior to elective surgery; do not resume for at least 4 weeks following major surgery and until wound is fully healed. Monitor BP every 2 weeks and treat appropriately if hypertension occurs; temporarily suspend until controlled; discontinue if hypertensive crisis/encephalopathy occurs. Discontinue if arterial thromboembolic events (eg, transient ischemic attack, cerebrovascular accident, angina pectoris) occur. Monitor for proteinuria; suspend if proteinuria ≥2grams per 24 hours; discontinue if nephrotic syndrome or thrombotic microangiopathy occurs. Monitor CBC with differential at baseline and prior to start of each cycle; delay until neutrophils ≥1.5x109/L. Risk of severe diarrhea and dehydration esp. in elderly (monitor). Discontinue if reversible posterior leukoencephalopathy syndrome occurs. Pregnancy (Cat. C). Use effective contraception during and up to 3 months after the last dose. Nursing mothers: not recommended.

Adverse Reaction(s):
Leukopenia, diarrhea, neutropenia, proteinuria, AST/ALT increased, stomatitis, fatigue, thrombocytopenia, hypertension, weight increased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, headache.

How Supplied:
Single-use vials (100mg/4mL)—1, 3
(200mg/8mL)—1

Last Updated:
8/30/2012