Approximately 40% of colorectal cancer patients will develop colorectal liver metastases (CRLM). The most effective approach to increase long-term survival is CRLM complete resection. Unfortunately, only 10 - 15% of CRLM are initially considered resectable. The objective response rates (ORR) after current first-line systemic chemotherapy (sys-CT) regimens range from 40 to 80% and complete resection rates (CRR) range from 25 to 50% in patients with initially unresectable CRLM. When CRLM patients are not amenable to complete resection after induction of sys-CT, ORRs obtained with second-line sys-CT are much lower (between 10 and 30%) and consequently CRRs are also low (< 10%). Hepatic arterial infusion (HAI) oxaliplatin may represent a salvage therapy in patients with CRLM unresectable after one or more sys-CT regimens with ORRs and CRRs up to 60 and 30%, respectively. This study is designed to evaluate the efficacy of an intensification strategy based on HAI oxaliplatin combined with sys-CT as the first-line treatment in patients with unresectable CRLM.

Inclusion Criteria:

1. Histologically confirmed colorectal cancer (CRC), and radiologic or histologic proof of liver metastasis.

2. Unresectability of the CRLM will be confirmed by a centralized multidisciplinary expert panel (composed of surgeons, radiologists, interventional radiologists and medical oncologists). The panel will review the CT scan and MRI of the patients (weekly web conference). Non-resectability criteria (one of the following criteria):

   • Upfront R0/R1 resection of all CRLM (that leaves at least two adequately perfused and drained segments) is not possible
   • Liver metastases in contact with major vessels of the remnant liver which would require resection of the vessel for an R0 resection (i.e., tumor involvement of main portal right and left portal veins, of the three main hepatic veins, or of the retrohepatic vena cava)

3. At least one measurable liver metastasis according to the RECIST v1.1

4. Age ≥18 years

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

6. Life expectancy of at least 3 months

7. Normal liver function International normalized ratio (INR) <1.5 ULN

8. Neutrophils >1500/mm³

9. Platelet >100 x 109/L (transfusion allowed)

10. Hemoglobin >9 g/dL (transfusion allowed)

11. Bilirubin <1.5 times the upper limit of normal values (ULN)

12. Aminotransferases <5 ULN, alkaline phosphatase <5 ULN

13. Calculated creatinine clearance >30 mL/min (Cockcroft and Gault formula)

14. Urine dipstick for proteinuria of less than 1+ is required within 7 days prior to study entry; if urine dipstick is >= 2+ then a 24 hour urine for protein must demonstrate =< 1 gm of protein in 24 hours to allow participation in the study; NOTE: Urinalysis is also acceptable

15. Informed consent signed by the patient or his/her legal representative

Exclusion Criteria:

1. Patient eligible for curative-intent treatment of CRLM (i.e. resection and/or thermoablation), according to the local multidisciplinary team and/or the central review. Definitive anatomical contraindication to complete surgical resection (any of the following criteria):

   • More than two lesions in all liver segments
   • Bilobar liver metastasis and more than three lesions >3 cm in the hepatic lobe the least affected (i.e. the future remnant liver)
   • Bilobar liver metastasis and disease liver extend >50%

2. Extrahepatic tumor disease (except ≤3 lung nodules <10 mm deemed amenable to curative-intent resection/thermoablation and non-resected primary tumor with no or mild symptoms)

3. Major surgical procedure within 28 days prior to study treatment start, or patients who have not fully recovered from major surgery

4. Radiotherapy to target lesion within 4 weeks before the study (A 2-week washout is permitted for palliative radiation.)

5. Has known uncontrolled active CNS metastases and/or carcinomatous meningitis

6. Peripheral neuropathy CTCAE v4.03 ≥ grade 2

7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

   Note: Participants with (A) basal cell carcinoma of skin, (B) squamous cell carcinoma of the skin, (C) low grade thyroid cancer or carcinoma in situ (eg, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

8. Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic systemic treatment and is allowed.

9. Uncontrolled hypertension or clinically active cardiovascular disease: for example, cerebrovascular accident or transient ischemic attack, unstable angina, myocardial infarction within 24 weeks prior to randomization. Have symptomatic congestive heart failure (CHF; New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia.

10. Have significant bleeding disorders, or evidence of bleeding diathesis or coagulopathy

11. Have had a significant bleeding episode from the gastrointestinal (GI) tract or lung

12. Have a history of GI perforation and/or fistula, or intra-abdominal abscess within 24 weeks prior to randomization.

13. Have a history of HNPCC syndrome or polyposis

14. Have experienced any arterial thromboembolic event or ongoing treatment with anticoagulants for therapeutic purpose within 24 weeks prior to randomization.

15. Has a known history of human immunodeficiency virus (HIV) infection

16. Are pregnant or breast feeding. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to first dose of study treatment. For women of childbearing potential and men, agreement to remain abstinent or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 30 days after the last dose of study drugs. Postmenopausal women is defined that : 1) must have been amenorrheic for at least 12 months, > 50 years old or 2) Age ≤ 50 years old and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range (>40 mIU/mL), 3) prior bilateral oophorectomy

17. Patients who are hypersensitive reaction to experimental drugs

18. Patients who are hypersensitive to CHO cell products or other recombinant or humanized antibodies

19. In case of contraindication of experimental drugs

20. Have any condition (eg, psychological, geographical, or medical) that does not permit compliance with the study and follow-up procedures or suggest that the patient is, in the investigator's opinion, not an appropriate candidate for the study.