Pharmacological Class:
Fusion protein.

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

Company
Sanofi and Regeneron
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:
10/31/2012
IMPORTANT SAFETY INFORMATION FOR ZALTRAP® (ZIV–AFLIBERCEPT) INJECTION FOR INTRAVENOUS INFUSION
WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING

Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage.

GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation.

Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed.
WARNINGS AND PRECAUTIONS
•Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.
Bleeding/hemorrhage (all grades) occurred in 38% of ZALTRAP/FOLFIRI patients vs. 19% of placebo/FOLFIRI patients. Grade 3–4 hemorrhagic events, including GI hemorrhage, hematuria, and post–procedural hemorrhage, occurred in 3% of ZALTRAP/FOLFIRI patients vs. 1% of placebo/FOLFIRI patients. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have occurred in patients receiving ZALTRAP.
Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage.
•GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP.
 
Across three clinical trials (colorectal, pancreatic, and lung cancer), GI perforation (all grades/Grade 3–4) occurred in 0.8% /0.8% of Zaltrap patients and 0.3% /0.2% for placebo patients.
Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP in patients who experience GI perforation.
•ZALTRAP impairs wound healing in animal models. Grade 3 compromised wound healing occurred in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI and none of the patients treated with placebo/FOLFIRI.
Discontinue ZALTRAP in patients with compromised wound healing.
Suspend ZALTRAP for at least 4 weeks prior to elective surgery and do not initiate/resume ZALTRAP until at least 4 weeks after major surgery and surgical wound is fully healed.
For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed.
•Fistula formation involving GI and non–GI sites occurs at a higher incidence in patients treated with ZALTRAP. Fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 1.5% (9/611) of ZALTRAP/FOLFIRI treated patients and 0.5% (3/605) of placebo/FOLFIRI patients. Grade 3 GI fistula formation occurred in 2 patients treated with Zaltrap (0.3%) and 1 placebo–treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula.
•An increased risk of Grade 3–4 hypertension has been observed in patients receiving ZALTRAP.
There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti–hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Of patients treated with ZALTRAP/FOLFIRI who developed Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment.

Monitor blood pressure at least every two weeks, treat with appropriate anti–hypertensive therapy, and continue monitoring blood pressure regularly during ZALTRAP treatment. Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy.
•Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. ATE occurred in 2.6% of ZALTRAP/FOLFIRI patients and 1.7% of placebo/FOLFIRI patients. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE.
•Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP.
•Proteinuria was reported in 62% of ZALTRAP/FOLFIRI patients compared to 41% of placebo/FOLFIRI patients. Grade 3–4 proteinuria occurred in 8% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies.
•Monitor proteinuria by urine dipstick analysis and urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria. Obtain a 24–hour urine collection in patients with a UPCR >1.
•Suspend ZALTRAP when proteinuria ≥2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours.
•If recurrent, suspend until proteinuria <2 grams/24hours and then reduce ZALTRAP dose to 2 mg/kg.
•Discontinue ZALTRAP if nephrotic syndrome or TMA develops.
•A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP.
•Grade 3–4 neutropenia occurred in 37% of ZALTRAP/FOLFIRI patients compared to 30% of placebo/FOLFIRI patients. Grade 3–4 febrile neutropenia occurred in 4% of ZALTRAP/FOLFIRI patients compared to 2% of placebo/FOLFIRI patients. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of ZALTRAP/FOLFIRI patients compared to 1.2% of placebo/FOLFIRI patients.
•Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ≥1.5 x 109/L.
•Incidence of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI.
•Grade 3–4 diarrhea was reported in 19% of ZALTRAP/FOLFIRI patients compared to 8% of placebo/FOLFIRI patients. Grade 3–4 dehydration was reported in 4% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients.
•The incidence of diarrhea is increased in patients ≥65 years of age compared to patients <65 years of age. Monitor closely.
•RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Confirm diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death.
ADVERSE REACTIONS
•The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between–arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.
•The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between–arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.
•Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.
•In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI.
PREGNANCY AND NURSING MOTHERS
•ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.
•It is not known whether ZALTRAP is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.