Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma

Abou‐Alfa, Ghassan K.; Qin, Shukui; Ryoo, Baek Yeol; Lu, Sheng–Nan; Yen, Chia‐Jui; Feng, Yin‐Hsun; Lim, Ho Yeong; Izzo, Francesco; Colombo, M.; Sarker, Debashis; Bolondi, Luigi; Vaccaro, Gina M.; Harris, William Proctor; Chen, Z.; Hubner, Richard A; Meyer, Tim; Sun, Weijing; Harding, James J.; Hollywood, Ellen; Ma, Jennifer; Wan, Peter J.; Ly, Michele; Bomalaski, John S.; Johnston, Amanda; Lin, Chun‐Yen; Chao, Yee; Chen, L. T.

doi:10.1093/annonc/mdy101

Cited by 165 publications

(105 citation statements)

References 23 publications

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“…Pegylated arginine deiminase (ADI-PEG20), an agent that can rapidly convert arginine to citrulline, was shown, both in vitro and in vivo, to exert anti-proliferative effects in argininosuccinate synthetase-deficient cancers, such as HCC. A Phase III trial of ADI-Peg 20 plus best supportive care vs. placebo plus best supportive care has been conducted in patients with advanced HCC and Child Pugh scores of 5-7 who failed to respond to or were intolerant of prior systemic therapy (26). This trial failed to reveal any survival benefit of ADI-Peg20 over placebo, although the drug was well-tolerated.…”

Section: Adi-peg20mentioning

confidence: 99%

Chemotherapy for hepatocellular carcinoma: current status and future perspectives

Ikeda

Morizane

Ueno

et al. 2017

Japanese Journal of Clinical Oncology

223

154

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Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). On the basis of the results of two pivotal Phase III placebo-controlled studies, sorafenib is currently acknowledged worldwide as the standard therapeutic agent for advanced HCC. Following the introduction of sorafenib for the treatment of HCC, Phase III trials of numerous other agents as first-line or second-line chemotherapy have been conducted to determine if any of these agents might offer superior survival benefit to sorafenib. In 2016, a clear survival benefit of regorafenib over placebo was demonstrated in HCC patients showing disease progression after sorafenib treatment. A year later, in 2017, lenvatinib has been shown to be non-inferior to sorafenib, in terms of the overall survival, in chemo-naïve patients with advanced HCC. More recently, promising outcomes have also been reported with new agents, such as nivolumab and cabozantinib. At present, various novel combination regimens including these agents are currently under development. Hepatic arterial infusion chemotherapy (HAIC) is frequently adopted for the treatment of locally advanced HCC in Japan, based on reports of high response rates and favorable long-term outcomes. Although some randomized controlled trials of HAIC plus sorafenib vs. sorafenib alone as first-line therapy have been conducted in patients with advanced HCC, no firm evidence of the superiority of one over the other has been established yet. In the future, demonstration of the survival advantage of HAIC and the recognition of HAIC as one of the standard treatments for patients with advanced HCC are expected.

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Section: Adi-peg20mentioning

confidence: 99%

Chemotherapy for hepatocellular carcinoma: current status and future perspectives

Ikeda

Morizane

Ueno

et al. 2017

Japanese Journal of Clinical Oncology

223

154

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“…Although initially tumors respond to ADI-PEG20, ASS1-deficient tumors eventually become resistant to this treatment by reexpressing ASS1 (12,14,(19)(20)(21). ADI-PEG20 has not been shown to have any single-agent activity, and clinical trials of ADI-PEG20 alone have been negative to date (22).…”

Section: Introductionmentioning

confidence: 99%

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Prudner

Rathore

Robinson

et al. 2019

Clinical Cancer Research

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Purpose: The response to acute and long-term arginine starvation results in a conditional adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. Here, we investigate the underlying biology of priming ASS1 À tumors with arginine deiminase (ADI-PEG20) before treatment with gemcitabine (GEM) and docetaxel (DTX) in sarcoma, pancreatic cancer, and melanoma cell lines.Experimental Design: ASS1 À tumor cell lines were treated to create LTAT (long-term ADI treated) cell lines (ASS1 þ ) and used for drug combination studies. Protein expression of ASS1, dCK, RRM2, E2F1, c-MYC, and hENT1 was measured. c-MYC activity was determined, live-cell immunofluorescent studies for hENT1, uptake assays of FITC-cytosine probe, and rescue studies with a c-MYC inhibitor were all determined in the presence or absence of the ADI-PEG20:GEM:DTX.Results: In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus. This resulted in an increase of hENT1 cell-surface expression and rendered the cells susceptible to GEM. In vivo studies demonstrate that the combination of ADI-PEG20:GEM: DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma.Conclusions: The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression. This finding is applicable to ASS1-deficient cancers that are currently treated with GEM.

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“…However, a trend of improved survival was observed in the subgroup of patients with low levels of circulating arginine (<10 µM). erefore, new studies will focus on the potential effect of this aspect [149].…”

Section: Clinical Trials Investigating the Use Of Np-based Therapy Fomentioning

confidence: 99%

The Dual Role of the Liver in Nanomedicine as an Actor in the Elimination of Nanostructures or a Therapeutic Target

Baboci

Capolla

Cintio

et al. 2020

Journal of Oncology

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e development of nanostructures for therapeutic purpose is rapidly growing, following the results obtained in vivo in animal models and in the clinical trials. Unfortunately, the potential therapeutic efficacy is not completely exploited, yet. is is mainly due to the fast clearance of the nanostructures in the body. Nanoparticles and the liver have a unique interaction because the liver represents one of the major barriers for drug delivery. is interaction becomes even more relevant and complex when the drug delivery strategies employing nanostructures are proposed for the therapy of liver diseases, such as hepatocellular carcinoma (HCC). In this case, the selective delivery of therapeutic nanoparticles to the tumor microenvironment collides with the tendency of nanostructures to be quickly eliminated by the organ. e design of a new therapeutic approach based on nanoparticles to treat HCC has to particularly take into consideration passive and active mechanisms to avoid or delay liver elimination and to specifically address cancer cells or the cancer microenvironment. is review will analyze the different aspects concerning the dual role of the liver, both as an organ carrying out a clearance activity for the nanostructures and as target for therapeutic strategies for HCC treatment.

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Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma

Abstract: www.clinicaltrials.gov (NCT 01287585).

Cited by 165 publications

References 23 publications

Chemotherapy for hepatocellular carcinoma: current status and future perspectives

Chemotherapy for hepatocellular carcinoma: current status and future perspectives

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

The Dual Role of the Liver in Nanomedicine as an Actor in the Elimination of Nanostructures or a Therapeutic Target

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