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Phase I clinical trial of decitabine (5-aza-2'-deoxycytidine) administered by hepatic arterial infusion in patients with unresectable liver-predominant metastases
  1. Yanina J L Jansen1,
  2. Gontran Verset2,
  3. Kelly Schats3,
  4. Pieter-Jan Van Dam4,
  5. Teofila Seremet1,
  6. Mark Kockx4,
  7. Jean-Luc B Van Laethem MD,PhD5,
  8. Bart Neyns1
  1. 1 Oncology, Universitair ziekenhuis Brussel, Brussel, Belgium
  2. 2 Oncology, Hopital Erasme, Bruxelles, Belgium
  3. 3 Anatomopathology, Histogenex, Antwerp, Belgium
  4. 4 HistoGeneX NV, Edegem, Belgium
  5. 5 Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
  1. Correspondence to Dr Yanina J L Jansen; yanina.jansen{at}uzbrussel.be

Abstract

DNA demethylating agents may increase the immunogenicity of malignant tumours and increase the efficacy of subsequent treatment with immune check point inhibitors. We investigated the safety of administrating the demethylating agent decitabine by hepatic arterial infusionin patients with unresectable liver meta stases from solid tumours in a dose escalation phase I clinical trial. A total of nine eligible patients were enrolled and initiated study treatment at three different dose levels (two patients at 10, four at 15 and six at a dose level of 20mg decitabine/m2/day) (per protocol there was no intent to escalate the dose above the median tolerated intravenous dose level). Decitabine was administered as a 1-hour hepatic arterial infusion on five consecutive days every 4 weeks. Intrapatient dose escalation was applied in five patients. Grades 1 and 2 haematological toxicity was the most frequent treatment-related adverse event. None of the patients experienced treatment-limiting adverse events. Expression analysis of 30 cancer test is antigens (CTA) in pretreatment and post-treatment biopsies from patients indicated an increased expression of 21 CTAs after treatment. There were no objective tumour responses on study treatment or during post study exposure to immune checkpoint therapy in four patients with uveal melanoma liver metastases. We conclude that the investigate d hepatic arterial administration regimen for decitabine can be safely applied, and a dose level of 20 mg/m2/day on five consecutive days every 4 weeks can be considered for further investigation in combinatorial immunotherapy regimens.

Trial registration number NCT02316028.

  • decitabine
  • liver metastases
  • hepatic arterial infusion

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Footnotes

  • Contributors All authors contributed to generation of data, recruitment of patients and review of the article.

  • Funding YJLJ was supported by a 1-year PhD scholarship grant from the Belgian Kom Op Tegen Kanker and the Willy Gepts funding (UZ Brussel). Decitabine was provided by Janssen-Cilag International NV free of charge.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This trial was approved by the Institutional Ethics Committee of the UZ Brussel (ClinicalTrials.gov identifier: NCT02316028).

  • Provenance and peer review Not commissioned; internally peer reviewed.

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