A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma
Background : Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbam...
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| creator | Chan, Stephen L. Cheng, Paul N.M. Liu, Angela M. Chan, Landon L. Li, Leung Chu, Cheuk M. Chong, Charing C.N. Lau, Yat M. Yeo, Winnie Ng, Kelvin K.C. Yu, Simon C.H. Mok, Tony S.K. Chan, Anthony W.H. |
| description | Background
: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC).
Methods
: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC.
Results
: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9–6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3–78.0 weeks) vs. 15.14 weeks (95% CI: 13.4–15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes.
Conclusions
: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. Trial registration number: NCT01092091. Date of registration: March 23, 2010. |
| doi_str_mv | 10.1007/s10637-021-01111-8 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8426309</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2570326982</sourcerecordid><originalsourceid>FETCH-LOGICAL-c540t-4f6fccaba58394177810cb704c25e81597757102198f4e1df1d13dbd6aabdd393</originalsourceid><addsrcrecordid>eNp9kc1vFCEYxonR2LX6D3gwJF68jPIxA8PFpGm0btKkl_ZMGHjZpc7CCDNN9uafLtut9eNQLhDe3_u8PDwIvaXkIyVEfiqUCC4bwmhDaF1N_wytaCd5Q0QrnqMVoUI2Qil5gl6VcksI4Uq2L9EJ530nOqVW6OcZnramAF6vsR1DDNaMuMyL2-MU8bwFDN7XS7vHJjo8ZXDBzuEO8BDSzuTvkHHyeILNfjQzOJzBpt0QookzNnlTD1W8Sm1hMnOyMI7LaDK2JtsQq8Jr9MKbscCbh_0U3Xz9cn3-rbm8ulifn102tmvJ3LReeGvNYLqeq5ZK2VNiB0layzroaaek7CStX6F63wJ1njrK3eCEMYNzXPFT9PmoOy3DDpyFOGcz6imH6mKvkwn630oMW71Jd7pvmeDkIPDhQSCnHwuUWe9COfgxEdJSNOsoZy2jjFb0_X_obVpyrPYqJQlnQvWsUuxI2ZxKyeAfH0OJPgSsjwHr6krfB6z72vTubxuPLb8TrQA_AqWW4gbyn9lPyP4CZvmzZA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2570326982</pqid></control><display><type>article</type><title>A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma</title><source>MEDLINE</source><source>Springer Online Journals</source><creator>Chan, Stephen L. ; Cheng, Paul N.M. ; Liu, Angela M. ; Chan, Landon L. ; Li, Leung ; Chu, Cheuk M. ; Chong, Charing C.N. ; Lau, Yat M. ; Yeo, Winnie ; Ng, Kelvin K.C. ; Yu, Simon C.H. ; Mok, Tony S.K. ; Chan, Anthony W.H.</creator><creatorcontrib>Chan, Stephen L. ; Cheng, Paul N.M. ; Liu, Angela M. ; Chan, Landon L. ; Li, Leung ; Chu, Cheuk M. ; Chong, Charing C.N. ; Lau, Yat M. ; Yeo, Winnie ; Ng, Kelvin K.C. ; Yu, Simon C.H. ; Mok, Tony S.K. ; Chan, Anthony W.H.</creatorcontrib><description>Background
: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC).
Methods
: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC.
Results
: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9–6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3–78.0 weeks) vs. 15.14 weeks (95% CI: 13.4–15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes.
Conclusions
: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. Trial registration number: NCT01092091. Date of registration: March 23, 2010.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-021-01111-8</identifier><identifier>PMID: 33856599</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Aged ; Aged, 80 and over ; Arginase ; Arginase - adverse effects ; Arginase - therapeutic use ; Arginine ; Argininosuccinate Synthase - biosynthesis ; Argininosuccinate Synthase - drug effects ; Biomarkers ; Biopsy ; Cancer ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - pathology ; Clinical outcomes ; Depletion ; Disease control ; Female ; Health services ; Hepatocellular carcinoma ; Humans ; Immunohistochemistry ; Intravenous administration ; Liver cancer ; Liver Neoplasms - drug therapy ; Liver Neoplasms - pathology ; Male ; Medicine ; Medicine & Public Health ; Middle Aged ; Oncology ; Ornithine ; Ornithine Carbamoyltransferase - biosynthesis ; Ornithine Carbamoyltransferase - drug effects ; Patients ; Pharmacology/Toxicology ; Phase II Studies ; Progression-Free Survival ; Quality of Life ; Recombinant Proteins - adverse effects ; Recombinant Proteins - therapeutic use ; Survival ; Tumors</subject><ispartof>Investigational new drugs, 2021-10, Vol.39 (5), p.1375-1382</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-4f6fccaba58394177810cb704c25e81597757102198f4e1df1d13dbd6aabdd393</citedby><cites>FETCH-LOGICAL-c540t-4f6fccaba58394177810cb704c25e81597757102198f4e1df1d13dbd6aabdd393</cites><orcidid>0000-0001-8998-5480</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10637-021-01111-8$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-021-01111-8$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33856599$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chan, Stephen L.</creatorcontrib><creatorcontrib>Cheng, Paul N.M.</creatorcontrib><creatorcontrib>Liu, Angela M.</creatorcontrib><creatorcontrib>Chan, Landon L.</creatorcontrib><creatorcontrib>Li, Leung</creatorcontrib><creatorcontrib>Chu, Cheuk M.</creatorcontrib><creatorcontrib>Chong, Charing C.N.</creatorcontrib><creatorcontrib>Lau, Yat M.</creatorcontrib><creatorcontrib>Yeo, Winnie</creatorcontrib><creatorcontrib>Ng, Kelvin K.C.</creatorcontrib><creatorcontrib>Yu, Simon C.H.</creatorcontrib><creatorcontrib>Mok, Tony S.K.</creatorcontrib><creatorcontrib>Chan, Anthony W.H.</creatorcontrib><title>A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Background
: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC).
Methods
: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC.
Results
: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9–6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3–78.0 weeks) vs. 15.14 weeks (95% CI: 13.4–15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes.
Conclusions
: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. Trial registration number: NCT01092091. Date of registration: March 23, 2010.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Arginase</subject><subject>Arginase - adverse effects</subject><subject>Arginase - therapeutic use</subject><subject>Arginine</subject><subject>Argininosuccinate Synthase - biosynthesis</subject><subject>Argininosuccinate Synthase - drug effects</subject><subject>Biomarkers</subject><subject>Biopsy</subject><subject>Cancer</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Clinical outcomes</subject><subject>Depletion</subject><subject>Disease control</subject><subject>Female</subject><subject>Health services</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Intravenous administration</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Oncology</subject><subject>Ornithine</subject><subject>Ornithine Carbamoyltransferase - biosynthesis</subject><subject>Ornithine Carbamoyltransferase - drug effects</subject><subject>Patients</subject><subject>Pharmacology/Toxicology</subject><subject>Phase II Studies</subject><subject>Progression-Free Survival</subject><subject>Quality of Life</subject><subject>Recombinant Proteins - adverse effects</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>Survival</subject><subject>Tumors</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp9kc1vFCEYxonR2LX6D3gwJF68jPIxA8PFpGm0btKkl_ZMGHjZpc7CCDNN9uafLtut9eNQLhDe3_u8PDwIvaXkIyVEfiqUCC4bwmhDaF1N_wytaCd5Q0QrnqMVoUI2Qil5gl6VcksI4Uq2L9EJ530nOqVW6OcZnramAF6vsR1DDNaMuMyL2-MU8bwFDN7XS7vHJjo8ZXDBzuEO8BDSzuTvkHHyeILNfjQzOJzBpt0QookzNnlTD1W8Sm1hMnOyMI7LaDK2JtsQq8Jr9MKbscCbh_0U3Xz9cn3-rbm8ulifn102tmvJ3LReeGvNYLqeq5ZK2VNiB0layzroaaek7CStX6F63wJ1njrK3eCEMYNzXPFT9PmoOy3DDpyFOGcz6imH6mKvkwn630oMW71Jd7pvmeDkIPDhQSCnHwuUWe9COfgxEdJSNOsoZy2jjFb0_X_obVpyrPYqJQlnQvWsUuxI2ZxKyeAfH0OJPgSsjwHr6krfB6z72vTubxuPLb8TrQA_AqWW4gbyn9lPyP4CZvmzZA</recordid><startdate>20211001</startdate><enddate>20211001</enddate><creator>Chan, Stephen L.</creator><creator>Cheng, Paul N.M.</creator><creator>Liu, Angela M.</creator><creator>Chan, Landon L.</creator><creator>Li, Leung</creator><creator>Chu, Cheuk M.</creator><creator>Chong, Charing C.N.</creator><creator>Lau, Yat M.</creator><creator>Yeo, Winnie</creator><creator>Ng, Kelvin K.C.</creator><creator>Yu, Simon C.H.</creator><creator>Mok, Tony S.K.</creator><creator>Chan, Anthony W.H.</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QO</scope><scope>7RV</scope><scope>7WY</scope><scope>7WZ</scope><scope>7X7</scope><scope>7XB</scope><scope>87Z</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8FL</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BEZIV</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FRNLG</scope><scope>FYUFA</scope><scope>F~G</scope><scope>GHDGH</scope><scope>K60</scope><scope>K6~</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>L.-</scope><scope>M0C</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQBIZ</scope><scope>PQBZA</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8998-5480</orcidid></search><sort><creationdate>20211001</creationdate><title>A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma</title><author>Chan, Stephen L. ; Cheng, Paul N.M. ; Liu, Angela M. ; Chan, Landon L. ; Li, Leung ; Chu, Cheuk M. ; Chong, Charing C.N. ; Lau, Yat M. ; Yeo, Winnie ; Ng, Kelvin K.C. ; Yu, Simon C.H. ; Mok, Tony S.K. ; Chan, Anthony W.H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-4f6fccaba58394177810cb704c25e81597757102198f4e1df1d13dbd6aabdd393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Arginase</topic><topic>Arginase - adverse effects</topic><topic>Arginase - therapeutic use</topic><topic>Arginine</topic><topic>Argininosuccinate Synthase - biosynthesis</topic><topic>Argininosuccinate Synthase - drug effects</topic><topic>Biomarkers</topic><topic>Biopsy</topic><topic>Cancer</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Clinical outcomes</topic><topic>Depletion</topic><topic>Disease control</topic><topic>Female</topic><topic>Health services</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Intravenous administration</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Oncology</topic><topic>Ornithine</topic><topic>Ornithine Carbamoyltransferase - biosynthesis</topic><topic>Ornithine Carbamoyltransferase - drug effects</topic><topic>Patients</topic><topic>Pharmacology/Toxicology</topic><topic>Phase II Studies</topic><topic>Progression-Free Survival</topic><topic>Quality of Life</topic><topic>Recombinant Proteins - adverse effects</topic><topic>Recombinant Proteins - therapeutic use</topic><topic>Survival</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chan, Stephen L.</creatorcontrib><creatorcontrib>Cheng, Paul N.M.</creatorcontrib><creatorcontrib>Liu, Angela M.</creatorcontrib><creatorcontrib>Chan, Landon L.</creatorcontrib><creatorcontrib>Li, Leung</creatorcontrib><creatorcontrib>Chu, Cheuk M.</creatorcontrib><creatorcontrib>Chong, Charing C.N.</creatorcontrib><creatorcontrib>Lau, Yat M.</creatorcontrib><creatorcontrib>Yeo, Winnie</creatorcontrib><creatorcontrib>Ng, Kelvin K.C.</creatorcontrib><creatorcontrib>Yu, Simon C.H.</creatorcontrib><creatorcontrib>Mok, Tony S.K.</creatorcontrib><creatorcontrib>Chan, Anthony W.H.</creatorcontrib><collection>SpringerOpen</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>ABI/INFORM Collection (ProQuest)</collection><collection>ABI/INFORM Global (PDF only)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest Business Premium Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Business Premium Collection (Alumni)</collection><collection>Health Research Premium Collection</collection><collection>ABI/INFORM Global (Corporate)</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Business Collection (Alumni Edition)</collection><collection>ProQuest Business Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ABI/INFORM Professional Advanced</collection><collection>ABI/INFORM global</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>One Business (ProQuest)</collection><collection>ProQuest One Business (Alumni)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chan, Stephen L.</au><au>Cheng, Paul N.M.</au><au>Liu, Angela M.</au><au>Chan, Landon L.</au><au>Li, Leung</au><au>Chu, Cheuk M.</au><au>Chong, Charing C.N.</au><au>Lau, Yat M.</au><au>Yeo, Winnie</au><au>Ng, Kelvin K.C.</au><au>Yu, Simon C.H.</au><au>Mok, Tony S.K.</au><au>Chan, Anthony W.H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2021-10-01</date><risdate>2021</risdate><volume>39</volume><issue>5</issue><spage>1375</spage><epage>1382</epage><pages>1375-1382</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>Background
: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC).
Methods
: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC.
Results
: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9–6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3–78.0 weeks) vs. 15.14 weeks (95% CI: 13.4–15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes.
Conclusions
: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. Trial registration number: NCT01092091. Date of registration: March 23, 2010.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>33856599</pmid><doi>10.1007/s10637-021-01111-8</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-8998-5480</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Investigational new drugs, 2021-10, Vol.39 (5), p.1375-1382 |
| issn | 0167-6997 1573-0646 |
| language | eng |
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| source | MEDLINE; Springer Online Journals |
| subjects | Aged Aged, 80 and over Arginase Arginase - adverse effects Arginase - therapeutic use Arginine Argininosuccinate Synthase - biosynthesis Argininosuccinate Synthase - drug effects Biomarkers Biopsy Cancer Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - pathology Clinical outcomes Depletion Disease control Female Health services Hepatocellular carcinoma Humans Immunohistochemistry Intravenous administration Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - pathology Male Medicine Medicine & Public Health Middle Aged Oncology Ornithine Ornithine Carbamoyltransferase - biosynthesis Ornithine Carbamoyltransferase - drug effects Patients Pharmacology/Toxicology Phase II Studies Progression-Free Survival Quality of Life Recombinant Proteins - adverse effects Recombinant Proteins - therapeutic use Survival Tumors |
| title | A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T17%3A00%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20phase%20II%20clinical%20study%20on%20the%20efficacy%20and%20predictive%20biomarker%20of%20pegylated%20recombinant%20arginase%20on%20hepatocellular%20carcinoma&rft.jtitle=Investigational%20new%20drugs&rft.au=Chan,%20Stephen%20L.&rft.date=2021-10-01&rft.volume=39&rft.issue=5&rft.spage=1375&rft.epage=1382&rft.pages=1375-1382&rft.issn=0167-6997&rft.eissn=1573-0646&rft_id=info:doi/10.1007/s10637-021-01111-8&rft_dat=%3Cproquest_pubme%3E2570326982%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2570326982&rft_id=info:pmid/33856599&rfr_iscdi=true |