Evaluation of the Safety and Efficacy of Treatment w/High Dose Melphalan Given Directly Into the Liver Followed by Treatment w/Approved Cancer Treatment or Approved Cancer Treatment Alone in Patients w/ Metastatic Colorectal Cancer w/Liver Dominant Disease

Prior treatment

• Child-Pugh Class B or C cirrhosis or evidence of clinically significant portal hypertension by history, endoscopy, or radiologic studies (large abdominal varices, prior history of varices by endoscopy).
• Active second malignancy, or has history of recently definitively treated invasive cancer in the past 2 years prior to enrolment with the exception of non-melanoma skin cancer.
• Use of immunosuppressive drugs.
• Inability to temporarily stop chronic anti-coagulation therapy.
• Received anti-cancer therapy including radiotherapy or investigational agent for any indication ≤ 30 days prior to randomization
• Previous treatment with trifluridine-tipiracil.
• Prior chemoembolization or radioembolization to the liver or prior hepatic arterial infusion therapy

Other illness

• New York Heart Association functional classification II, III or IV or active cardiac condition(s), including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease that create(s) undue risks of undergoing general anesthesia.
• History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia.
• History of bleeding disorders, presence of brain metastases, or other intracranial abnormalities found on baseline radiologic imaging that would put them at risk for bleeding with anti-coagulation.
• Known varices at risk of bleeding, including medium or large esophageal or gastric varices, active peptic ulcer, or history of recent hemoptysis.
• Active bacterial infections with systemic manifestations.
• Active viral infection, including Hepatitis B and Hepatitis C infection. NOTE: Patients with anti-hepatitis B core antibody (HBc) positive, or hepatitis B surface antigen (HBsAg) but DNA negative are allowed exception(s).
• Severe allergic reaction to iodine contrast that cannot be controlled by premedication with antihistamines and steroids.
• History of or known hypersensitivity to melphalan or the components of the melphalan/HDS system.
• History of known hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia.
• Uncontrolled endocrine disorder including diabetes mellitus, hypothyroidism, or hyperthyroidism.
• History of allergic reactions attributed to compounds of similar composition to trifluridine/tipiracil or any of its excipients.
• History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients.
• History of hypersensitivity to Chinese Hamster Ovary cell products or other recombinant human or humanized antibodies.
• Contraindications to bevacizumab, including uncontrolled hypertension, history of active fistula or bowel perforation (unless in the setting of a resected primary), history of CVA or arterial thrombotic event in the last 1 year, or history of venous thrombotic event in the last 30 days.
• Evidence of hepatic vein or portal vein thrombosis

Other

• Peritoneal lesions or large abdominal masses.
• Hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption.

• Histologically confirmed diagnosis of metastatic colorectal cancer and histologically or cytologically proven CRC metastases that occupy 50% or less of the liver parenchyma.
• Patient has liver-dominant metastatic disease. Liver-dominant is defined as the majority of total tumor burden is located in the liver, and the liver lesions are not resectable or treatable with ablation or are associated with extrahepatic disease that makes surgical intervention non-curative.
• Disease in the liver must be measurable (per RECIST v.1.1 guidelines) by computed tomography (CT) and/or magnetic resonance imaging (MRI).
• If there is evidence of extrahepatic metastatic disease, it is limited, and the life-threatening component of disease is in the liver. Limited extrahepatic disease is defined in this protocol as follows: up to 5 tumor lesions in the lung with longest diameter not greater than 2 cm and/or up to 5 lymph nodes that measure 2 cm or less per lesion; solitary lesions definitively treated with no sign of progression in the last 6 months.
• Scans used to determine eligibility (CT scan of the chest/abdomen/pelvis and MRI of the liver) must be performed within 28 days prior to randomization.
• Previous treatment and progressed on or following, or intolerant to, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and/or an anti-EGFR therapy if RAS wild-type.
• ECOG PS of 0-1 within 14 days prior to randomization.