The purpose of this study is to find out if giving reolysin in combination with FOLFOX6/ bevacizumab can offer better results than standard therapy with FOLFOX6/ bevacizumab.

Researchers doing this study also want to evaluate the side effects of reolysin when given together with FOLFOX6/ bevacizumab.

Inclusion Criteria:

• Patients must have a histological diagnosis of colorectal adenocarcinoma.
• All patients must have a formalin fixed paraffin embedded tissue block (from their primary or metastatic tumour) available for translational studies and must have provided informed consent for the release of the block.
• Presence of clinically and/or radiologically documented disease. All radiology studies must be performed within 28 days prior to randomization (within 35 days if negative). All patients must have measurable disease as defined by RECIST 1.1.

The criteria for defining measurable disease are as follows:

Chest X-ray ≥ 20 mm CT/MRI scan (with slice thickness of < 5 mm) ≥ 10 mm longest diameter Physical exam (using calipers) ≥ 10 mm Lymph nodes by CT scan ≥ 15 mm measured in short axis

• Patients must have advanced and or metastatic disease, for which no curative therapy exists and for which systemic therapy is indicated.
• ECOG performance of 0, 1 or 2.
• Age ≥ 18 years of age.
• Previous Therapy

Surgery:

Previous major surgery is permitted provided that it has been at least 21days prior to patient randomization and that wound healing has occurred.

Chemotherapy:

Patients may NOT have received any prior cytotoxic chemotherapy for advanced or metastatic disease. Prior adjuvant fluoropyrimidine-based therapy is permitted provided completed at least one year prior to enrollment and the regimen did not include oxaliplatin or bevacizumab. Exceptions may be made for low dose chemotherapy given as a radiosensitizing agent.

Other Therapy:

Patients may have received other therapies including immunotherapy, or with signal transduction inhibitors, providing that the patient has recovered from all reversible drug related toxicity (with the exception of alopecia) and adequate washout period has been met.

Radiation:

Prior external beam radiation is permitted provided a minimum of 4 weeks has elapsed between the last dose and enrollment to the trial. Exceptions may be made for low dose, non-myelosuppressive radiotherapy after consultation with NCIC CTG.

• Laboratory Requirements (must be done within 7 days prior to randomization)

Hematology:

Granulocytes (AGC) ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L

Biochemistry:

Serum creatinine ≤ 1.5 x ULN Total bilirubin ≤ 1.0 x ULN (unless elevated secondary to conditions such as Gilbert's disease) ALT and AST ≤ 3 x ULN (Note: ≤ 5 x ULN if documented liver metastasis) Proteinuria < 2g/24 hrs (screen using spot testing; if ≥ grade 2 repeat with mid-stream urine - if still ≥ grade 2 then urine collection for 24 hours to confirm <2g/24hrs)

• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.

Patients who cannot give informed consent (i.e. mentally incompetent patients, or those physically incapacitated such as comatose patients) are not to be recruited into the study. Patients competent but physically unable to sign the consent form may have the document signed by their nearest relative or legal guardian. Each patient will be provided with a full explanation of the study before consent is requested.

• Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 2 hour's driving distance) placed on patients being considered for this trial. Investigators must assure themselves that the patients registered on this trial will be available for complete documentation of the treatment, adverse events, response assessment and follow-up.
• Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life (EORTC QLQ-C30) in either English or French. The baseline assessment must already have been completed. Inability (illiteracy in English or French, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible. The baseline assessment must be completed within 14 days prior to randomization.
• In accordance with NCIC CTG policy, protocol treatment is to begin within 5 working days of patient randomization.

Exclusion Criteria:

• Patients with a history of other malignancies, except for adequately treated non-melanoma skin cancer or solid tumours curatively treated with no evidence of disease for ≥ 3 years. (Please call NCIC CTG if any questions about the interpretation of this criterion).
• Patients who are on immunosuppressive therapy or have known HIV infection or active hepatitis B or C.
• Patients with active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol.
• Patients with significant cardiac (including uncontrolled hypertension) or pulmonary disease, or active CNS disease or infection.
• Patients are not eligible if they have a known hypersensitivity to the study drug(s) or their components.
• Patients with history of central nervous system metastases or untreated spinal cord compression.
• Patients who have had prior treatment with oxaliplatin or bevacizumab, who have contraindications to treatment with 5FU (for e.g. known DPD deficiency or severe cardiac disease), and or neuropathy > grade 1.
• Patients who are not sterile unless they use an adequate method of birth control.