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

NCT02316028 | Completed Phase 1

• 1 other identifier: UZB-BN-2013-002
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

Brief 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

Conditions

Liver Metastasis; Colorectal Cancer

Keywords

decitabine; colorectal cancer; hepatic arterial infusion

Outcome Measures

Primary Outcomes (1)

• toxicity of escalating doses of decitabine administered by HAI

  : to establish the recommended dose of decitabine administered by hepatic arterial infusion in patients with unresectable liver-predominant metastases from colorectal cancer

  2years

Secondary Outcomes (5)

• overall survival

  5years

• progression free survival

  5 years

• best objective tumor response

  5 years

• measuring Global DNA methylation of tumoral DNA

  2years

• measuring Global DNA methylation of cell free DNA

  2years

Study Arms (1)

decitabine

EXPERIMENTAL

administration of decitabine by hepatic arterial infusion * Accrual of patients and dosing of decitabine will be guided by a traditional 3+3 design using an accelerated titration for the first three dose levels. * Proposed dose levels: 1. 10 mg/m2 per course 2. 15 mg/m2 per course 3. 20 mg/m2 per course

Drug: Decitabine

Interventions

Decitabine DRUG

administration of decitabine by hepatic arterial infusion * Accrual of patients and dosing of decitabine will be guided by a traditional 3+3 design using an accelerated titration for the first three dose levels. * Proposed dose levels: 1. 10 mg/m2 per course 2. 15 mg/m2 per course 3. 20 mg/m2 per course

Also known as: Dacogen

decitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Universitair Ziekenhuis Brussel: lead
• Janssen, LP: collaborator

Study Sites (2)

UZ Brussel

Jette, Brabant, 1090, Belgium

Location

UZ Brussel

Brussels, 1090, Belgium

Location

Related Publications (1)

• Jansen YJL, Verset G, Schats K, Van Dam PJ, Seremet T, Kockx M, Van Laethem JB, Neyns B. Phase I clinical trial of decitabine (5-aza-2'-deoxycytidine) administered by hepatic arterial infusion in patients with unresectable liver-predominant metastases. ESMO Open. 2019 Mar 5;4(2):e000464. doi: 10.1136/esmoopen-2018-000464. eCollection 2019.

  PMID: 30962963 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Decitabine

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Bart Neyns, PhD, MD

  Universitair Ziekenhuis Brussel

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2014
• First Posted: December 12, 2014
• Study Start: March 1, 2014
• Primary Completion: December 1, 2016
• Study Completion: July 1, 2017
• Last Updated: October 27, 2017

Record last verified: 2017-10

Locations

BE (2)