Phase I:Decitabine by Hepatic Arterial Infusion(HAI) in Unresectable Liver Metastases Colorectal Cancer (CRC)

This clinical trial will recruit eligible patients diagnosed with unresectable liver-predominant colorectal cancer metastases who have experience progression of their disease following standard of care treatment.

Unless patients already dispose of a hepatic arterial catheter, they will undergo placement of a permanent hepatic artery catheter (by laparoscopic surgery). During this surgical procedure a biopsy will be made of the colorectal cancer liver metastasis.

Decitabine will be administered as a daily 1-hour IV infusion on 5 consecutive days, every 4weeks.

Two weeks after the first day of administration of decitabine, a CT-guided biopsy a liver metastasis will be performed in order to obtain tumor tissue for histopathological analysis and DNA/RNA extraction for the purposes of methylation specific Polymerase Chain Reaction (PCR) and reverse transcriptase PCR for assessment of demethylation and expression of cancer-testis antigen encoding genes.

Blood samples for collection of "cell-free DNA" and White Blood Cell (WBC ) for the purpose of DNA/RNA extraction and analysis by methylation specific PCR and reverse transcriptase PCR for assessment of demethylation and expression of cancer-testis antigen encoding genes will be obtained weekly after decitabine treatment.

The dose of decitabine will be escalated in subsequent patient cohorts enrolled to this phase I trial (see rules for dose escalation).

Study treatment will be continued until unacceptable toxicity, progressive disease or patient refusal.

Inclusion criteria

• Histological documentation of colorectal adenocarcinoma CRC stage IV with predominant unresectable liver metastases and at least one measurable metastatic liver lesion
• Performance status WHO criteria of < 2.
• Laboratory values: absolute neutrophil count (ANC) count > 1500 /mm³, Platelet count > 100 000 /mm³, Lymphocytes > 800 /mm³, Serum creatinine < 2.0 mg/dl or creatinine clearance >40 ml/min, Serum bilirubin < 2.0 mg/dl
• Progressive disease following standard of care palliative systemic chemotherapy
• able to give written informed consent.

Exclusion criteria

• No prior radiotherapy to all target liver lesions
• No previous history of gastric or hepatobiliary surgery (except for simple cholecystectomy, No concurrent liver disease or other serious medical disease or condition
• No concomitant use of other investigational drugs.
• No pre-existing neuropathy with a severity of > grade 1 in the WHO toxicity scale.
• No previous or concurrent malignancies except for adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma of the skin or any other malignancy given potentially curative treatment more than 5 years before study entry
• No pregnant or breast-feeding female patients, use of an effective contraceptive if the risk of conception exists during study treatment.
• No candidate for the resection of all CRC metastases with curative intent.