Aflibercept and FOLFOX6 Treatment for Previously Untreated Stage IV Colorectal Cancer

This phase II trial studies how well giving aflibercept together with combination chemotherapy works in treating patients with previously untreated colon or rectal cancer that is metastatic or locally advanced and cannot be removed by surgery. Aflibercept may stop the growth of colon or rectal cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving aflibercept together with combination chemotherapy may kill more tumor cells

PRIMARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of patients with untreated metastatic colorectal cancer (mCRC) receiving the combination of modified leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX6) (mFOLFOX6) and aflibercept.

SECONDARY OBJECTIVES:

I. To evaluate the objective response rate (complete response \[CR\] + partial response \[PR\]) and the disease control rate (CR + PR + stable disease \[SD\]), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, of patients with untreated mCRC receiving the combination of mFOLFOX6 and aflibercept.

II. To evaluate overall survival of patients with untreated mCRC receiving the combination of mFOLFOX6 and aflibercept.

III. To further characterize the safety and toxicity of the combination of mFOLFOX6 and aflibercept, including 60 day all-cause mortality.

IV. To describe patients with mCRC whose disease is rendered resectable as a consequence of therapy with the combination of mFOLFOX 6 and aflibercept.

TERTIARY OBJECTIVES:

I. To assess the use of dynamic imaging modalities including dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) to evaluate changes in vascular permeability and FDG avidity and correlate with clinical efficacy (PFS, overall survival \[OS\], and response by RECIST 1.1).

II. To evaluate circulating levels of vascular endothelial growth factor A (VEGFA), phosphatidylinositol glycan anchor biosynthesis, class F (PlGF), soluble vascular endothelial growth factor receptor 2 (VEGF-R2), chemokine (C-X-C motif) ligand 12 (CXCL12) and chemokine (C-X-C motif) receptor 4 (CXCR4) as potential biomarkers for efficacy of aflibercept.

III. To evaluate for the presence of VEGF single nucleotide polymorphisms (SNPs) and whether any SNP(s), when detected, may be predictive of efficacy and/or toxicity of aflibercept.

IV. To assess microvessel density/tumor blood flow, capillary permeability and vessel normalization by tumor biopsy pre and post treatment with aflibercept.

V. To evaluate the presence of hypertension as a predictive biomarker for clinical efficacy of aflibercept.

OUTLINE:

Patients receive aflibercept intravenously (IV) over 1 hour followed by oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5-15 minutes and then continuously over 46 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Eligibility Criteria:
Inclusion Criteria:

* Histologically confirmed adenocarcinoma of colorectal origin that is metastatic or locally advanced and unresectable
* Measurable disease, as defined by RECIST 1.1 criteria: one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 10 mm with spiral computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) malignant lymph nodes will be considered measurable if they are \>= 15 mm in short axis
* Must not have received any prior systemic therapy for metastatic or locally advanced CRC; prior VEGF inhibitors are not allowed
* Prior adjuvant therapy for CRC including fluoropyrimidines either alone or in combination with oxaliplatin is allowed, provided that all therapy was completed \>= 12 months from cancer recurrence, therapy duration was =\< 6 months, and all prior toxicities have completely resolved (residual grade 1 neuropathy is allowed)
* Life expectancy \>= 12 weeks
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Hemoglobin \>= 9 g/dL (blood transfusion permitted to attain this value)
* Absolute neutrophil count \>= 1,500/uL
* Platelets \>= 100,000/uL
* Total bilirubin =\< 2 x institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN (may be =\< 5x ULN if increase is due to metastatic disease)
* Creatinine =\< 1.5 x institutional ULN or creatinine clearance \>= 60 mL/min/1.73 m2 for patients with creatinine levels above institutional U
* Urine protein:creatinine ratio (UPCR) \< 1 or \< 500 mg protein/24 hr
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* May not be receiving any other investigational agents
* Patients who have received any prior locoregional therapy for metastatic disease (e.g. radiofrequency/microwave ablation, Yttrium-90 radioembolization, transarterial chemoembolization, or surgical resection) are excluded
* Patients with known or suspected brain metastases, carcinomatous meningitis, uncontrolled seizure disorder, active intracranial bleeding or active neurologic disorder are excluded
* Patients with an active second primary malignancy or history of malignancy within the 5 years of enrollment are excluded, with the exception of non-melanoma skin cancers and cervical cancer which has been treated with curative therapy
* Grade \>= 2 sensory neuropathy at the time of enrollment
* Major surgery within 4 weeks of study start date; the surgical incision should be fully healed prior to initiation of aflibercept
* Female or male patients of reproductive capacity unwilling to use methods appropriate to prevent pregnancy are excluded; effective contraception is required for at least 3 months following the last administration of aflibercept
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled hypertension (blood pressure \[BP\] must be well controlled \< 160/90), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, or any condition that the principal investigator (PI) feels would make the patient ineligible
* Positive pregnancy screening test with a minimum sensitivity of 25 IU/L of human chorionic gonadotropin (hCG) within 72 hours of registration; breastfeeding women are also excluded
* History of pulmonary embolus within 3 months or deep venous thrombosis (DVT) within 4 weeks of enrollment; patients on anticoagulation must be on a stable dose of warfarin with a therapeutic-range international normalized ratio (INR) or on a stable dose of low molecular weight heparin
* Active congestive heart failure (New York Heart Association \[NYHA\] class II-IV)
* History of an arterial thrombotic vascular event including cerebrovascular accident (CVA), myocardial infarction (MI), unstable angina, coronary or peripheral arterial bypass graft, or transient ischemic attack (TIA) within 6 months
* Serious or non-healing wound, ulcer or bone fracture at the time of medication administration
* History of treatment-resistant peptic ulcer disease, erosive esophagitis, gastritis, or diverticulitis within 3 months
* History of gastrointestinal (GI) perforation within 5 years; current or prior intestinal fistulas are also excluded
* Known chronic infectious disease including human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)
* History of major hemorrhage including gastrointestinal bleeding (grade 2-4), pulmonary hemorrhage, or clinically significant hemoptysis (\> 1 tsp in 24 hours) within the last 5 years; patients with underling conditions that predispose to bleeding, such as bleeding diathesis, known esophageal varices, or tumor involving major vessels, are also excluded
* Inability to understand or comply with study protocol
* Known hypersensitivity to Chinese hamster ovary cell products or to recombinant human or murine antibodies, or any of the treatments in this protocol