ZALTRAP (Page 4 of 5)

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of 6 mg per 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.

12.3 Pharmacokinetics

Plasma concentrations of free and VEGF-bound ziv-aflibercept were measured using specific enzyme-linked immunosorbent assays (ELISA). Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetics in the dose range of 2 mg per kg to 9 mg per kg. 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 per kg every two weeks.

Elimination

Following a dose of 4 mg per kg every two weeks administered intravenously, the elimination half-life of free ziv-aflibercept was approximately 6 days (range 4–7 days).

Specific Populations

Based on a population pharmacokinetic analysis, age, race, and sex 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.

Patients with hepatic impairment

Based on a population pharmacokinetic analysis which included patients with mild (total bilirubin >1 to 1.5 times ULN and any AST, n=63) and moderate (total bilirubin >1.5 to 3 times ULN and any AST, n=5) hepatic impairment, there was no effect of total bilirubin, AST, and alanine aminotransferase on the clearance of free ziv-aflibercept. There are no data available for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

Patients with renal impairment

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.

Drug Interaction Studies

No clinically meaningful interaction was found between ziv-aflibercept and irinotecan or fluorouracil based on cross-study comparisons and population pharmacokinetic analyses.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

13.2 Animal Toxicology and/or Pharmacology

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.

14 CLINICAL STUDIES

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

Figure 1
(click image for full-size original)
Table 2: Main Efficacy Outcome Measures for VELOUR *
ZALTRAP/FOLFIRIN=612Placebo/FOLFIRIN=614
*
PFS (based on tumor assessment by the IRC): Significance threshold is set to 0.0001.
Stratified on ECOG Performance Status (0 vs 1 vs 2) and Prior Bevacizumab (yes vs no)
Overall objective response rate by IRC
Overall Survival
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-value0.0032
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-value0.0001

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.

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