Study of Chemoembolisation Using Irinotecan Bead Prior to Surgery in Metastatic Colorectal Cancer (PARAGON-II)

The objective of this study is to evaluate the safety and efficacy of Irinotecan Bead in the neoadjuvant treatment (i.e. the Irinotecan Bead is administered prior to surgery) of resectable liver metastases from colorectal cancer.

The Primary Endpoint of this study is Tumour resectability at surgery. Secondary Endpoints:

1. Safety assessed by SAE and AE monitoring (NCI CTCAE v3.0)
2. Tumour response assessed by imaging (RECIST and necrosis)
3. Viable residual tumour assessed by pathological evaluation of resected liver tissue.
4. Recurrence (time and site) following resection
5. Correlation of tumour response by imaging and pathology

Inclusion criteria

1. Presence of potentially resectable colorectal cancer liver metastases, with less than 60% liver tumour replacement. The consulting surgeon, according to local practice, will determine resectability.
2. Patients having undergone complete resection of the primary tumour without gross or microscopic evidence of residual disease (R0), or the primary tumour is considered R0 resectable at screening.
3. Age: 18-80 years.
4. ECOG Status ≤2.
5. No previous irinotecan-containing chemotherapy for advanced disease.
6. Previous chemotherapy is allowed (unless it contained irinotecan), but must have ended at least one month prior to study entry.
7. Presence of adequate contraception in fertile (M/F) patients. Pregnant or lactating women are excluded.
8. Absence of any other previous malignancy other than adequately treated in situ carcinoma of the cervix or non-melanoma skin cancer (unless there has been a disease-free interval of at least 10 years).
9. Patients should not have participated in another clinical trial with any investigational drug in the 30 days prior to enrolment.

10. Absence of:

    • Peripheral neuropathy (CTC > grade 1)
    • Uncontrolled congestive heart failure or angina pectoris, or hypertension or arrhythmia.
    • History of significant neurologic or psychiatric disorders
    • Active infection
11. Written informed consent according to ICH/EU GCP, and any applicable local, national or international regulations.
12. Patients with liver-dominant disease, defined as ≥80% of the tumour body burden confined to the liver. Unilobar disease, or bilobar disease suitable for treatment in a single chemoembolisation procedure, with a maximum of 4 lesions.
13. Hematologic function: WBC ≥3.0 x 10*9/L, platelets ≥100 x 10*9/L, Absolute neutrophil count > 1.5 x 10*9/l.

14. Adequate organ function as measured by:

    1. Serum creatinine ≤2 x upper limit of normal (ULN).
    2. Serum transaminases (AST & ALT) ≤5 x ULN.
    3. Total bilirubin ≤1.5 x ULN.
    4. Prothrombin time >50% of normal.

Exclusion criteria

1. Extrahepatic metastases constituting >20% of tumour body burden.

2. Contraindications to irinotecan:

   1. Chronic inflammatory bowel disease and/or bowel obstruction.
   2. History of severe hypersensitivity reactions to irinotecan hydrochloride trihydrate.
   3. Severe bone marrow failure.
   4. Concomitant use with St John's Wort.
3. Active bacterial, viral or fungal infection within 72 hours of study entry.
4. Allergy to contrast media that cannot be managed with standard care.

5. Any contraindication for hepatic embolisation procedures:

   1. porto-systemic shunt.
   2. hepatofugal blood flow.
   3. severe atheromatosis.
6. Contraindication to hepatic artery catheterisation, such as a patient with severe peripheral vascular disease precluding catheterisation.
7. Other significant medical or surgical condition, or any medication or treatment regimens, that would place the patient at undue risk, that would preclude the safe use of chemoembolisation or would interfere with study participation.