A phase I and pharmacokinetic study of afilbercept with FOLFIRI: comparison of Chinese and Caucasian populations.

Background This study assessed the preliminary safety, pharmacokinetics (PK) and anti-tumor effects of aflibercept in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in Chinese patients with previously-treated advanced solid malignancies. Patients and Methods This open-label single-arm Phase I study conducted at two centers in China included adult (≥18 years) patients with metastatic or unresectable solid malignancies who had received ≥1 prior treatment. Patients received aflibercept 4 mg/kg IV on Day 1 followed by FOLFIRI over Days 1 and 2 every 2 weeks, and were assessed for safety, tumor response, PK parameters and immunogenicity. Post-hoc analyses included calculation of progression-free survival (PFS) for patients with colorectal cancer (CRC). Results A total of 20 patients were enrolled. The most common Grade 3/4 adverse events included neutropenia (35%), hypertension (30%), stomatitis (20%) and proteinuria (20%), and no anti-aflibercept antibodies were detected. Six patients achieved a partial response, and in 15 patients with CRC median PFS was 5.95 months (95% CI: 5.29-8.77). Free aflibercept remained in excess of VEGF-bound aflibercept for the majority of the study treatment duration. The mean free aflibercept values for Cmax (64.8 µg/mL) AUC (291 µg.day/mL), CL (0.92 L/day) and Vss (5.9 L) were similar to those measured in Caucasian patients. The addition of aflibercept did not influence the PK of the chemotherapy agents. Conclusion For Chinese patients with pre-treated advanced solid malignancies, 4 mg/kg of aflibercept in combination with FOLFIRI was well-tolerated, demonstrated preliminary anti-tumor activity and had a PK profile consistent with that in Caucasian patients.

Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial.

PURPOSE: In North America, no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan, bolus fluorouracil (FU), and leucovorin (IFL). PATIENTS AND METHODS: Patients with metastatic colorectal cancer who progressed after IFL therapy were randomly assigned to bolus and infusional FU and leucovorin (LV5FU2), single-agent oxaliplatin, or the combination (FOLFOX4). This planned interim analysis evaluated objective response rate (RR), time to tumor progression (TTP), and alleviation of tumor-related symptoms (TRS) in an initial cohort of patients. RESULTS: Between November 2000 and September 2001, 463 patients from 120 sites in North America were randomly assigned to treatment. FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy. Objective RRs determined by an independent radiology panel were 9.9% for FOLFOX4 versus 0% for LV5FU2 (Fisher's exact test, P <.0001). Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (two-sided, stratified log-rank test, P <.0001). Relief of TRS occurred in 33% of patients treated with FOLFOX4 versus 12% of patients treated with LVFU2 (chi2 test, P <.001). Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy. Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate. CONCLUSION: For patients with metastatic colorectal cancer, second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR, TTP, and relief of TRS.