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.

Clinical Studies
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 m2 IV infusion over 90 minutes and leucovorin (dl racemic) 400 mg per m² intravenous infusion over 2 hours at the same time on day 1 using a Y-line, followed by 5-FU 400 mg per m² intravenous bolus, followed by 5-FU 2400 mg per m² 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 outcome measures*  Placebo/FOLFIRI
(N=614) Zaltrap/FOLFIRI
(N=612)
*
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 (%) 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)* 

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
Planned subgroup analyses for overall survival based on stratification factors a