Trial design:

• Phase III, FOLFIRI versus FOLF(HA)iri (the FOLFIRI regimen with "Hyaluronic acid-Irinotecan" or "HA-Irinotecan") regimen.

• Patients with mCRC (metastatic colorectal cancer), 2nd/3rd line irinotecan naïve.

• Randomized 1:1, double-blinded, multi-centre, multi-national (Australia, Bulgaria, Poland, Serbia, Russia, Ukraine and the United Kingdom).

• Dosing regimen:

  • Irinotecan (180 mg/m2) or HA-Irinotecan (180 mg/m2), IV, over 90 minutes, day 1 (in patients > 75 years of age, the irinotecan and HA-Irinotecan dose in must be reduced to 150 mg/m2).
  • Leucovorin, 400 mg/m2, or levoleucovorin, 200 mg/m2, IV over 90 minutes with irinotecan.
  • 5-fluorouracil (5-FU), 400 mg/m2 IV bolus day 1, then 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46-48 hours) continuous infusion.
  • Repeat every 2 weeks for 8 months.

• Patient accrual over approximately 12-14 months.

• Monitoring to 18 months post-randomization.

• 390 patients.

• Progression Free Survival (PFS) primary endpoint.

• Safety analysis on the initial 20 patients.

Inclusion Criteria:

• Metastatic colorectal cancer with disease progression after first or second line chemotherapy
• Irinotecan naïve.
• ECOG performance status of 0 or 1.
• Measurable disease, i.e. at least one measurable metastatic lesion (spiral CT or MRI).
• Histological proof of colorectal cancer.
• 18 years of age and older.
• Adequately recovered from and at least 4 weeks after recent surgery or chemotherapy.
• Women of child-bearing potential (WOCBP) and male partners of WOCBP must agree to use adequate contraception.
• Patient consent obtained and signed according to local and/or national ethics.
• CT or MRI scan of chest/abdomen/pelvis within 21 days prior to randomization.
• Hematology done within 14 days prior to randomization.
• Chemistry done within 14 days prior to randomization.

Exclusion Criteria:

• History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for > 5 years.
• Locally advanced or recurrent disease only.
• Unsuitability for irinotecan including known Gilbert's syndrome, active inflammatory bowel disease or chronic diarrhea greater than or equal to grade 2.
• Abdominal or pelvic radiation therapy within the last 12 months.
• Women who are pregnant or breastfeeding.
• Any condition (e.g., psychological, geographical) that would render the protocol treatment dangerous.
• Significant cardiac disease.
• Untreated or symptomatic brain or central nervous system (CNS).
• Presence of pleural effusion or ascites requiring therapeutic thoracocentesis or paracentesis.
• Current partial or complete bowel obstruction.
• Concomitant active infection.
• Enrolled in any other investigational trial, unless treatment in that trial has been discontinued at least 30 days prior to signing the Informed Consent for the ACO-002 study.