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

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.

SUBMITTER: Mei Q

PROVIDER: S-EPMC4599300 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Mei Qian Q Chen Meixia M Lu Xuechun X Li Xiang X Duan Feng F Wang Maoqiang M Luo Guangbin G Han Weidong W

Oncotarget 20150601 18

<h4>Purpose</h4>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.<h4>Experimental design</h4>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, progr ...[more]

PMID: 25895027

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Project description:Expressed by cancer stem cells of various epithelial cell origins and hepatocellular carcinoma (HCC), CD133 is an attractive therapeutic target for HCC. The marker CD133 is highly expressed in endothelial progenitor cells (EPC). EPCs circulate in increased numbers in the peripheral blood of patients with highly vascularized HCC and contribute to angiogenesis and neovascularization. This phase II study investigated CD133-directed chimeric antigen receptor (CAR) T (CART-133) cells in adults with HCC. Patients with histologically confirmed and measurable advanced HCC and adequate hematologic, hepatic, and renal functions received CART-133 cell infusions. The primary endpoints were safety in phase I and progression-free survival (PFS) and overall survival (OS) in phase II. Other endpoints included biomarkers for CART-133 T cell therapy. Between June 1, 2015, and September 1, 2017, this study enrolled 21 patients who subsequently received CART-133 T cells across phases I and II. The median OS was 12 months (95% CI, 9.3-15.3 months) and the median PFS was 6.8 months (95% CI, 4.3-8.4 months). Of 21 evaluable patients, 1 had a partial response, 14 had stable disease for 2 to 16.3 months, and 6 progressed after T-cell infusion. The most common high-grade adverse event was hyperbilirubinemia. Outcome was correlated with the baseline levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR2), stromal cell-derived factor (SDF)-1, and EPC counts. Changes in EPC counts, VEGF, SDF-1, sVEGFR2, and interferon (IFN)-γ after cell infusion were associated with survival. In patients with previously treated advanced HCC, CART-133 cell therapy demonstrates promising antitumor activity and a manageable safety profile. We identified early changes in circulating molecules as potential biomarkers of response to CART-133 cells. The predictive value of these proangiogenic and inflammatory factors as potential biomarkers of CART-133 cell therapy in HCC will be explored in prospective trials. This study is registered at ClinicalTrials.gov (NCT02541370).

Project description:BackgroundAn increasing number of studies is now devoted to immunotherapy of cancer. We evaluated the clinical benefit of hepcortespenlisimut-L (Hepko-V5 [formerly known as V5])-an oral therapeutic vaccine designated by the United States Food and Drug Administration (FDA) as an orphan drug for treatment of hepatocellular carcinoma (HCC). V5 was initially developed by us in 2002 to treat hepatitis B or C viral infections and liver cirrhosis.MethodsThe outcome of open-label Phase II trial of daily dose of V5 pill was analyzed retrospectively. Over a period of 5 years, 75 patients with advanced HCC were enrolled, consisting of 29 (38.7%) females and 46 (61.3%) males with a median age of 60 years (mean 61.6±8.1 years). Out of these, 23 (30.7%) had hepatitis B and 34 (45.3%) had hepatitis C infections, including 9 (12%) with dual infection, 4 (5.3%) negative for both viruses, and 5 (6.7%) without established viral diagnosis. Most patients (94.7%) had underlying liver cirrhosis of varying severity.ResultsAfter a median of 2 months of treatment, 50 out of 75 patients had experienced a decline in serum levels of the tumor marker, alpha-fetoprotein (AFP) (66.7%; P=0.006 by Wilcoxon signed rank test). Baseline median AFP levels were 245.2 IU/mL (mean 4,233; range 7.2-92,407; 95% confidence interval [CI] 1,186-7,280) and post-treatment values were 102.3 IU/mL (mean 2,539; range 0.9-54,478; 95% CI 503-4,575). The decrease in AFP was correlated either with tumor clearance or regression on computed tomography scans. The median overall survival time could not be established since 68 out of 75 (90.7%) patients were still alive after median follow-up of 12 months (mean 15±9.7; range 7-59; 95% CI 12.8-17.2). The first patient in this study received immunotherapy 5 years ago and still remains in complete remission. None of the patients experienced any serious adverse effects or toxicity.ConclusionThe results indicate that hepcortespenlismut-L is a safe, effective, and fast-acting immunomodulatory intervention for HCC. The Phase III, randomized, double-blind, placebo-controlled trial is now initiated at the Mongolian National Cancer Center to confirm these promising findings.

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Dataset Information

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

Publications

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

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