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

• Status: Completed
• Trial end date: 2017-07-01
• Target enrollment: 0
• Participant gender: All

Summary

Despite the advances in the medical treatment of unresectable liver metastases from colorectal cancer there is currently no curative treatment option available for these patients. Decitabine is a cytidine analog with proven anti-neoplastic activity in patients with acute myeloid leukemia and myelodysplastic syndromes. Decitabine causes demethylation of the DNA strands of replicating cells. Hereby decitabine treatment demethylates the promoter regions of tumor suppressor- and cancer testis antigen encoding genes leading to expression of these genes by the cancer cells. The hepatic arterial route for administration of cytotoxic drugs has been widely explored in treatment of colorectal cancer liver metastases because these metastases depend for their blood flow from this artery (as opposed to the normal liver tissue that is mainly dependent from the portal vein). By investigating the administration of decitabine by hepatic arterial infusion the investigators intend to explore the potential advantage of minimizing the systemic exposure (and toxicity) and maximizing the concentration of decitabine within the liver metastasis. The primary objective of this phase I will be to establish the recommended dose for decitabine by HAI for further use in phase II trials. The most important secondary objective will be to document the effect of decitabine by HAI on the expression of cancer testis antigens by the colorectal cancer cells, serving as a reference for potential further exploration of decitabine by HAI in combination with cancer immunotherapy

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Universitair Ziekenhuis Brussel
• Collaborator: Janssen, LP
• Treatments: Azacitidine; Decitabine

Criteria

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.