Ziv-Aflibercept Followed by Ziv-Aflibercept, Fluorouracil, and Leucovorin Calcium in Treating Patients With Stage IV Colorectal Cancer

PRIMARY OBJECTIVES: I. To determine the progression-free survival during the first phase of the study (PFS1) in patients with metastatic colorectal cancer treated with single agent ziv-aflibercept after progressing on leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX) and leucovorin calcium, fluorouracil, irinotecan hydrochloride (FOLFIRI) with bevacizumab +/- cetuximab or panitumumab. II. To determine the progression-free survival (PFS2) in patients with metastatic colorectal cancer treated with ziv-aflibercept and 5-fluorouracil (fluorouracil), after progressing on ziv-aflibercept alone. SECONDARY OBJECTIVES: I. Overall survival. II. Response rate. III. Incidence and nature of adverse events. IV. Growth modulation index (ratio of PFS2/PFS1). TERTIARY OBJECTIVES: I. To determine relevant biomarkers which can distinguish patients with a progression free survival greater than 3 months on single agent ziv-aflibercept (tumor vascular endothelial growth factor \[VEGF\], vascular endothelial growth factor receptor \[VEGFR\]1 and 2, baseline plasma phosphatidylinositol glycan anchor biosynthesis, class F \[PlGF\]). II. Plasma levels of VEGF-A, B, C, D, intercellular adhesion molecule 1 (ICAM), chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha) (Gro alpha), hepatocyte growth factor (HGF), stem cell growth factor beta (SCGF beta) prior to treatment and with each cycle of therapy. III. Single nucleotide polymorphisms (SNPs) of VEGFA, VEGFR1 \& 2 \& 3, interleukin (IL)8, angiopoietin-2 (Ang2), IL-6, ICAM, PlGF, neuropilin (NRP)1 \& 2, chemokine (C-X-C motif) receptor 2 (CXCR2) and others in the angiogenic pathway. IV. Tumor messenger ribonucleic acid (mRNA) expression levels of VEGF B, C, D, VEGFR 3; NRP 1, 2, and VEGF isoforms on biopsy specimens taken at trial initiation and upon disease progression and addition of 5-FU. V. Correlation of biomarkers with toxicity of ziv-aflibercept alone and with 5-FU. OUTLINE: PHASE I: Patients receive ziv-aflibercept intravenously (IV) over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of progression, patients proceed to Phase II. PHASE II: Patients receive ziv-aflibercept IV over 1 hour, leucovorin calcium IV over 1 minute, and fluorouracil IV over 46 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.