Combination Chemotherapy and Bevacizumab With or Without PRI-724 in Treating Patients With Newly Diagnosed Metastatic Colorectal Cancer

• Histologically confirmed stage IV colorectal adenocarcinoma without any prior systemic treatment
• Signed informed consent prior to initiation of any study-specific procedure or treatment, including consent to provide blood samples for correlative studies and to obtain a tumor biopsy during the study
• Representative tumor tissue specimens (paraffin block preferred)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Able to comply with the protocol, including tissue and blood sampling
• Leukocytes >= 3,000 per mm\^3
• Absolute neutrophil count >= 1,500 per mm\^3
• Platelet count >= 100,000 per mm\^3
• Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level)
• Serum creatinine value \< upper limit of normal (ULN) or creatinine clearance of >= 60 mL/min according to Cockgroft-Gault formula
• Urine for proteinuria should be \< 2 +; patients discovered to have >= 2 + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate \< 1 g of protein in 24 hours
• Serum total bilirubin \< 1.5 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN (\< 5 x ULN if there is evidence of hepatic involvement by malignant disease)
• International normalized ratio =\< 1.5 and activated prothrombin time =\< 1.5 x ULN for patients not receiving anti-coagulation therapy
• The use of full-dose oral or parenteral anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits (according to the medical standard of the enrolling institution), and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment
• Female patients should not be pregnant or breast-feeding

• A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

  • Has not undergone hysterectomy or bilateral oophorectomy; OR
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 months)
• Female patients with childbearing potential should agree to use effective, nonhormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) during the study and for a period of at least 3 months following the last administration of study drug
• Female patients with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 72 hours prior to administration of any treatment
• Male patients must agree to use effective contraception during the study and for a period of at least 6 months following the last administration of study drugs, even if they have been surgically sterilized
• Patients with treated brain metastases are eligible for study participation; patients may not receive ongoing treatment with steroids at screening; anticonvulsants (at stable dose) are allowed; treatment for brain metastases may be whole-brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician; radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization
• Archival tumor tissue sample (i.e., representative tumor tissue specimen in paraffin block [preferred] or at least 20 unstained slides) must be requested and available prior to study entry
• Patients must have biopsiable tumor and agree to study biopsy

Exclusion Criteria:

• Any prior systemic treatment for metastatic colorectal cancer
• Known hypersensitivity to any of the components of PRI-724, fluorouracil (5-FU), oxaliplatin or bevacizumab
• Adjuvant systemic treatment for colorectal cancer within last 12 months
• Radiotherapy to any site for any reason within 28 days prior to treatment
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Sensory peripheral neuropathy > Common Terminology Criteria for Adverse Events (CTCAE) grade 1
• Corrected QT (QTc) interval > 470 msec (females) or > 450 msec (males)
• Active hepatitis B, hepatitis C
• History of arterial thromboembolic events
• History of abdominal fistula formation, gastrointestinal perforation, or abdominal abscess within six months
• History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding
• Patients must not be pregnant or nursing
• Surgery (including open biopsy), significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during study treatment
• Any hemorrhage or bleeding event >= CTCAE grade 3 within 4 weeks prior to the start of study medication
• Non-healing wound, ulcer, or bone fracture
• Inadequately controlled hypertension (systolic blood pressure [SBP] > 150mmHg, diastolic blood pressure [DBP] > 100mg Hg)
• Renal insufficiency requiring dialysis
• Known positivity for human immunodeficiency virus (HIV)
• Malignancies other than colorectal adenocarcinoma within 5 years prior to treatment, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent
• Clinically detectable (by physical exam) third-space fluid collections (e.g. ascites or pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry
• Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization
• Minor surgery, including insertion of an indwelling catheter, within 24 hours prior to the first bevacizumab infusion
• Current or recent (within 10 days prior to first dose of bevacizumab) use of aspirin (> 325 mg/day); prophylactic and therapeutic use of anticoagulants is allowed, e.g., warfarin (1 mg once daily [QD]) for catheter prophylaxis and prophylactic low molecular weight heparin (i.e., enoxaparin [40 mg QD])
• Clinically significant (i.e., active) cardiovascular disease (e.g., cerebrovascular accident or myocardial infarction [MI] within 6 months prior to randomization), unstable angina, congestive heart failure (CHF) (New York Heart Association [NYHA] class >= NII), or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with administration of study treatment