An open-label, single-arm, phase I/II study of lower-dose decitabine based therapy in patients with advanced hepatocellular carcinoma

Qian Mei,Xiang Li,Meixia Chen,Maoqiang Wang,Guangbin Luo,Weidong Han,Feng Duan,Xuechun Lu

doi:10.18632/oncotarget.3677

Qian Mei, Xiang Li + Show 6 more

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https://doi.org/10.18632/oncotarget.3677

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Abstract

We conducted this phase I/II clinical trial to determine the safety and efficacy of lower-dose decitabine based therapy in pretreated patients with advanced HCC. Patients with advanced HCC were eligible. The administered dose of decitabine was 6 mg/m2/d intravenously on days 1 to 5 of a 28-day cycle. Additional therapies were given based on their disease progression status. The endpoint was to ensure the safety, hepatotoxicity, clinical responses, progression-free survival (PFS) and pharmacodynamics assay of lower-dose decitabine. Fifteen patients were enrolled. The favorable adverse events and liver function profiles were observed. The most beneficial responses were 1 complete response (CR), 6 stable disease (SD) and 8 progressive disease (PD). MRI liver scans post-treatment indicated a unique and specific characteristic. The immunohistochemistry result from the liver biopsy exhibited noteworthy CTL responses. Median PFS was 4 months (95% CI 1.7, 7), comparing favorably with existing therapeutic options. Expression decrement of DNMT1 and global DNA hypomethylation were observed in PBMCs after lower-dose decitabine treatment. The lower-dose decitabine based treatment resulted in beneficial clinical response and favorable toxicity profiles in patients with advanced HCC. The prospective evaluations of decitabine administration schemes and tumor tissue-based pharmacodynamics effect are warranted in future trials.

Highlights

Decitabine (5-Aza-2′-deoxycytidine) is an epigenetic drug that inhibits DNA methylation [1] and has been approved by the Food and Drug Administration for the treatment of myelodysplastic syndrome and acute myelogenous leukemia [2]
The lower-dose decitabine based treatment resulted in beneficial clinical response and favorable toxicity profiles in patients with advanced Hepatocellular carcinoma (HCC)
The prospective evaluations of decitabine administration schemes and tumor tissue-based pharmacodynamics effect are warranted in future trials

Summary

Introduction

Decitabine (5-Aza-2′-deoxycytidine) is an epigenetic drug that inhibits DNA methylation [1] and has been approved by the Food and Drug Administration for the treatment of myelodysplastic syndrome and acute myelogenous leukemia [2]. A clinical trial, conducted in MDS using 0.1-0.2 mg/kg (3.5-7 mg/m2) decitabine, revealed the decreased toxicity and complete hematologic and cytogenetic remission, with an overall response rate of 44% [5], suggesting the usage of a very low dosage of decitabine could be a potential compelling and effective form of therapy for solid cancer [3, 6,7,8]. Based on this hypothesis, we registered a phase I/II clinical trial for lower-dose decitabine therapy, named the “Lower Dose Decitabine Based Therapy in Patients with Refractory and/or Chemotherapy Resistant Solid Tumors or B Cell Lymphomas” (ClinicalTrials.gov identifier NCT01799083).

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