No studies have been conducted to evaluate carcinogenicity or mutagenicity of ziv-aflibercept.
Ziv-aflibercept impaired reproductive function and fertility in monkeys. In a 6-month repeat-dose toxicology study in sexually mature monkeys, ziv-aflibercept inhibited ovarian function and follicular development, as evidenced by: decreased ovary weight, decreased amount of luteal tissue, decreased number of maturing follicles, atrophy of uterine endometrium and myometrium, vaginal atrophy, abrogation of progesterone peaks and menstrual bleeding. Alterations in sperm morphology and decreased sperm motility were present in male monkeys. These effects were observed at all doses tested including the lowest dose tested, 3 mg per kg. Reversibility was observed within 18 weeks after cessation of treatment. Systemic exposure (AUC) with a 3 mg per kg per dose in monkeys was approximately 0.6 times the AUC in patients at the 4 mg per kg dose.
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.
The efficacy of ZALTRAP was evaluated in VELOUR (NCT00561470), a randomized (1:1), 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. Patients were randomized to receive either ZALTRAP 4 mg per kg intravenously over 1 hour on day 1 or placebo in combination with FOLFIRI (irinotecan 180 mg/m2 intravenously over 90 minutes and leucovorin [dl racemic] 400 mg/m2 intravenously over 2 hours at the same time on day 1 using a Y-line, followed by fluorouracil 400 mg/m2 as an intravenous bolus and then by fluorouracil 2400 mg/m2 as a 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. Randomization was stratified by the Eastern Cooperative Oncology Group performance status (PS) (0 versus 1 versus 2) and according to prior therapy with bevacizumab (yes or no). The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR).
Demographics characteristics were similar between treatment arms. A total of 1226 patients were randomized, 612 to the ZALTRAP arm and 614 to the placebo arm. 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 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.
Efficacy results are summarized in Figure 1 and Table 2.
Figure 1: Kaplan-Meier Curves of Overall Survival for VELOUR
|Number of deaths, n (%)||403 (65.8%)||460 (74.9%)|
|Median overall survival (95% CI) (months)||13.50 (12.52, 14.95)||12.06 (11.07, 13.08)|
|Stratified Hazard ratio (95% CI)||0.817 (0.714, 0.935)|
|Stratified Log-Rank test p-value||0.0032|
|Progression Free Survival (PFS)*|
|Number of events, n (%)||393 (64.2%)||454 (73.9%)|
|Median PFS (95% CI) (months)||6.90 (6.51, 7.20)||4.67 (4.21, 5.36)|
|Stratified Hazard ratio (95% CI)||0.758 (0.661, 0.869)|
|Stratified Log-Rank test p-value †||0.00007|
|Overall Response Rate (ORR)|
|ORR (CR+PR) (95% CI)‡||19.8% (16.4%, 23.2%)||11.1% (8.5%, 13.8%)|
|Stratified Cochran-Mantel-Haenszel test p-value||0.0001|
Planned subgroup analyses for overall survival based on stratification factors at randomization yielded an HR of 0.86 (95% CI: 0.68, 1.1) in patients who received prior bevacizumab and an HR of 0.79 (95% CI: 0.67, 0.93) in patients without prior bevacizumab exposure.
ZALTRAP (ziv-aflibercept) injection is a clear, colorless to pale-yellow solution supplied in single-dose vials with a concentration of 25 mg/mL.
NDC 0024-5840-01: carton containing one single-dose vial of 100 mg/4 mL (25 mg/mL)
NDC 0024-5841-01: carton containing one single-dose vial of 200 mg/8 mL (25 mg/mL)
Store ZALTRAP vials in a refrigerator at 2°C to 8°C (36°F to 46°F). Keep the vials in the original outer carton to protect from light. Discard unused portion.
- Inform patients that ZALTRAP can cause severe bleeding and advise patients to contact their health care provider for bleeding or symptoms of bleeding, including lightheadedness [see Warnings and Precautions (5.1)].
Gastrointestinal Perforation and Fistula Formation
- Advise patients to immediately contact their health care provider for signs and symptoms of gastrointestinal perforation or fistula [see Warnings and Precautions (5.2, 5.4)].
Impaired Wound Healing
- Advise patients that ZALTRAP may impair wound healing. Instruct patients to discuss any planned surgical procedure (including tooth extractions) with all their healthcare providers. [see Warnings and Precautions (5.3)].
- Inform patients that ZALTRAP can cause or exacerbate existing hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions (5.5)].
Arterial Thromboembolic Events
- Inform patients of an increased risk of ATE [see Warnings and Precautions (5.6)].
- Advise patients that they will need to undergo regular laboratory tests to monitor protein in their urine [see Warnings and Precautions (5.7)].
Neutropenia and Neutropenic Complications
- Advise patients to notify their health care provider of fever or other signs of infection [see Warnings and Precautions (5.8)].
Diarrhea and Dehydration
- Advise patients to notify the health care provider of severe diarrhea, vomiting, or severe abdominal pain [see Warnings and Precautions (5.9)].
Posterior Reversible Leukoencephalopathy Syndrome
- Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions (5.10)].
Advise pregnant women and females of reproductive potential:
- of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].
- to use effective contraception during treatment with ZALTRAP and for 1 month following the last dose [see Use in Specific Populations (8.3)].
- Advise women not to breastfeed during treatment with ZALTRAP and for 1 month following the last dose [see Use in Specific Populations (8.2)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
U.S. License No. 1752
ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc.
©2020 sanofi-aventis U.S. LLC
PRINCIPAL DISPLAY PANEL — 100 mg/4 mL Vial Carton
100 mg/4 mL
For intravenous infusion only.
Not to be administered by
Hyperosmotic, must be diluted.
Single-dose vial.Discard unused portion
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