A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer
Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against secon...
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| Veröffentlicht in: | Clinical cancer research 2020-03, Vol.26 (5), p.1009-1016 |
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| creator | Oza, Amit M Matulonis, Ursula A Alvarez Secord, Angeles Nemunaitis, John Roman, Lynda D Blagden, Sarah P Banerjee, Susana McGuire, William P Ghamande, Sharad Birrer, Michael J Fleming, Gini F Markham, Merry Jennifer Hirte, Hal W Provencher, Diane M Basu, Bristi Kristeleit, Rebecca Armstrong, Deborah K Schwartz, Benjamin Braly, Patricia Hall, Geoff D Nephew, Kenneth P Jueliger, Simone Oganesian, Aram Naim, Sue Hao, Yong Keer, Harold Azab, Mohammad Matei, Daniela |
| description | Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer.
Patients received either G+C (guadecitabine 30 mg/m
s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS).
Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively;
= 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group;
= 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group.
Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection. |
| doi_str_mv | 10.1158/1078-0432.CCR-19-1638 |
| format | Article |
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Patients received either G+C (guadecitabine 30 mg/m
s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS).
Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively;
= 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group;
= 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group.
Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-19-1638</identifier><identifier>PMID: 31831561</identifier><language>eng</language><publisher>United States</publisher><subject><![CDATA[Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Azacitidine - administration & dosage ; Azacitidine - analogs & derivatives ; Carboplatin - administration & dosage ; Deoxycytidine - administration & dosage ; Deoxycytidine - analogs & derivatives ; Doxorubicin - administration & dosage ; Doxorubicin - analogs & derivatives ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Epigenesis, Genetic - drug effects ; Female ; Humans ; Middle Aged ; Neoplasm Recurrence, Local - drug therapy ; Neoplasm Recurrence, Local - mortality ; Neoplasm Recurrence, Local - pathology ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - mortality ; Ovarian Neoplasms - pathology ; Paclitaxel - administration & dosage ; Patient Safety ; Polyethylene Glycols - administration & dosage ; Survival Rate ; Topotecan - administration & dosage ; Treatment Outcome]]></subject><ispartof>Clinical cancer research, 2020-03, Vol.26 (5), p.1009-1016</ispartof><rights>2019 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-94be9e362875bcd824d3b6cb5cbefd21b167032c3b10a1017bb7047bc31df8ce3</citedby><cites>FETCH-LOGICAL-c408t-94be9e362875bcd824d3b6cb5cbefd21b167032c3b10a1017bb7047bc31df8ce3</cites><orcidid>0000-0001-8783-3491 ; 0000-0002-8864-5932 ; 0000-0003-2888-4146 ; 0000-0003-3567-3494</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31831561$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oza, Amit M</creatorcontrib><creatorcontrib>Matulonis, Ursula A</creatorcontrib><creatorcontrib>Alvarez Secord, Angeles</creatorcontrib><creatorcontrib>Nemunaitis, John</creatorcontrib><creatorcontrib>Roman, Lynda D</creatorcontrib><creatorcontrib>Blagden, Sarah P</creatorcontrib><creatorcontrib>Banerjee, Susana</creatorcontrib><creatorcontrib>McGuire, William P</creatorcontrib><creatorcontrib>Ghamande, Sharad</creatorcontrib><creatorcontrib>Birrer, Michael J</creatorcontrib><creatorcontrib>Fleming, Gini F</creatorcontrib><creatorcontrib>Markham, Merry Jennifer</creatorcontrib><creatorcontrib>Hirte, Hal W</creatorcontrib><creatorcontrib>Provencher, Diane M</creatorcontrib><creatorcontrib>Basu, Bristi</creatorcontrib><creatorcontrib>Kristeleit, Rebecca</creatorcontrib><creatorcontrib>Armstrong, Deborah K</creatorcontrib><creatorcontrib>Schwartz, Benjamin</creatorcontrib><creatorcontrib>Braly, Patricia</creatorcontrib><creatorcontrib>Hall, Geoff D</creatorcontrib><creatorcontrib>Nephew, Kenneth P</creatorcontrib><creatorcontrib>Jueliger, Simone</creatorcontrib><creatorcontrib>Oganesian, Aram</creatorcontrib><creatorcontrib>Naim, Sue</creatorcontrib><creatorcontrib>Hao, Yong</creatorcontrib><creatorcontrib>Keer, Harold</creatorcontrib><creatorcontrib>Azab, Mohammad</creatorcontrib><creatorcontrib>Matei, Daniela</creatorcontrib><title>A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer.
Patients received either G+C (guadecitabine 30 mg/m
s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS).
Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively;
= 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group;
= 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group.
Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Azacitidine - administration & dosage</subject><subject>Azacitidine - analogs & derivatives</subject><subject>Carboplatin - administration & dosage</subject><subject>Deoxycytidine - administration & dosage</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Doxorubicin - administration & dosage</subject><subject>Doxorubicin - analogs & derivatives</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Epigenesis, Genetic - drug effects</subject><subject>Female</subject><subject>Humans</subject><subject>Middle Aged</subject><subject>Neoplasm Recurrence, Local - drug therapy</subject><subject>Neoplasm Recurrence, Local - mortality</subject><subject>Neoplasm Recurrence, Local - pathology</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - mortality</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Paclitaxel - administration & dosage</subject><subject>Patient Safety</subject><subject>Polyethylene Glycols - administration & dosage</subject><subject>Survival Rate</subject><subject>Topotecan - administration & dosage</subject><subject>Treatment Outcome</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kN1Kw0AQRhdRbK0-grIP4NadbH4vS6i1UGgp9TrsbibtSrMJm0TRax_cxFphYOZizjfMIeQe-BQgiJ-ARzHjvvCmabplkDAIRXxBxhAEERNeGFz283lnRG6a5o1z8IH712QkIBYQhDAm3zO6lTavSvOFOd0cZIN0uaQ7Z-SRVgWd12aPFluj6caZ0tg9_TDtgS46maM2rVTGIu0TaCqdquqjbI2lfW1-p65kDhvTtNK2j3SLunMObUvX77K_YHvIanS35KqQxwbv_vqEvD7Pd-kLW60Xy3S2YtrnccsSX2GCIvTiKFA6jz0_FyrUKtAKi9wDBWHEhaeFAi6BQ6RUxP1IaQF5EWsUExKccrWrmsZhkdX9T9J9ZsCzwWo2GMsGY1lvNYMkG6z23MOJqztVYv5PnTWKH6o0dQ8</recordid><startdate>20200301</startdate><enddate>20200301</enddate><creator>Oza, Amit M</creator><creator>Matulonis, Ursula A</creator><creator>Alvarez Secord, Angeles</creator><creator>Nemunaitis, John</creator><creator>Roman, Lynda D</creator><creator>Blagden, Sarah P</creator><creator>Banerjee, Susana</creator><creator>McGuire, William P</creator><creator>Ghamande, Sharad</creator><creator>Birrer, Michael J</creator><creator>Fleming, Gini F</creator><creator>Markham, Merry Jennifer</creator><creator>Hirte, Hal W</creator><creator>Provencher, Diane M</creator><creator>Basu, Bristi</creator><creator>Kristeleit, Rebecca</creator><creator>Armstrong, Deborah K</creator><creator>Schwartz, Benjamin</creator><creator>Braly, Patricia</creator><creator>Hall, Geoff D</creator><creator>Nephew, Kenneth P</creator><creator>Jueliger, Simone</creator><creator>Oganesian, Aram</creator><creator>Naim, Sue</creator><creator>Hao, Yong</creator><creator>Keer, Harold</creator><creator>Azab, Mohammad</creator><creator>Matei, Daniela</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-8783-3491</orcidid><orcidid>https://orcid.org/0000-0002-8864-5932</orcidid><orcidid>https://orcid.org/0000-0003-2888-4146</orcidid><orcidid>https://orcid.org/0000-0003-3567-3494</orcidid></search><sort><creationdate>20200301</creationdate><title>A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer</title><author>Oza, Amit M ; Matulonis, Ursula A ; Alvarez Secord, Angeles ; Nemunaitis, John ; Roman, Lynda D ; Blagden, Sarah P ; Banerjee, Susana ; McGuire, William P ; Ghamande, Sharad ; Birrer, Michael J ; Fleming, Gini F ; Markham, Merry Jennifer ; Hirte, Hal W ; Provencher, Diane M ; Basu, Bristi ; Kristeleit, Rebecca ; Armstrong, Deborah K ; Schwartz, Benjamin ; Braly, Patricia ; Hall, Geoff D ; Nephew, Kenneth P ; Jueliger, Simone ; Oganesian, Aram ; Naim, Sue ; Hao, Yong ; Keer, Harold ; Azab, Mohammad ; Matei, Daniela</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-94be9e362875bcd824d3b6cb5cbefd21b167032c3b10a1017bb7047bc31df8ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Azacitidine - administration & dosage</topic><topic>Azacitidine - analogs & derivatives</topic><topic>Carboplatin - administration & dosage</topic><topic>Deoxycytidine - administration & dosage</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Doxorubicin - administration & dosage</topic><topic>Doxorubicin - analogs & derivatives</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Epigenesis, Genetic - drug effects</topic><topic>Female</topic><topic>Humans</topic><topic>Middle Aged</topic><topic>Neoplasm Recurrence, Local - drug therapy</topic><topic>Neoplasm Recurrence, Local - mortality</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - mortality</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Paclitaxel - administration & dosage</topic><topic>Patient Safety</topic><topic>Polyethylene Glycols - administration & dosage</topic><topic>Survival Rate</topic><topic>Topotecan - administration & dosage</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oza, Amit M</creatorcontrib><creatorcontrib>Matulonis, Ursula A</creatorcontrib><creatorcontrib>Alvarez Secord, Angeles</creatorcontrib><creatorcontrib>Nemunaitis, John</creatorcontrib><creatorcontrib>Roman, Lynda D</creatorcontrib><creatorcontrib>Blagden, Sarah P</creatorcontrib><creatorcontrib>Banerjee, Susana</creatorcontrib><creatorcontrib>McGuire, William P</creatorcontrib><creatorcontrib>Ghamande, Sharad</creatorcontrib><creatorcontrib>Birrer, Michael J</creatorcontrib><creatorcontrib>Fleming, Gini F</creatorcontrib><creatorcontrib>Markham, Merry Jennifer</creatorcontrib><creatorcontrib>Hirte, Hal W</creatorcontrib><creatorcontrib>Provencher, Diane M</creatorcontrib><creatorcontrib>Basu, Bristi</creatorcontrib><creatorcontrib>Kristeleit, Rebecca</creatorcontrib><creatorcontrib>Armstrong, Deborah K</creatorcontrib><creatorcontrib>Schwartz, Benjamin</creatorcontrib><creatorcontrib>Braly, Patricia</creatorcontrib><creatorcontrib>Hall, Geoff D</creatorcontrib><creatorcontrib>Nephew, Kenneth P</creatorcontrib><creatorcontrib>Jueliger, Simone</creatorcontrib><creatorcontrib>Oganesian, Aram</creatorcontrib><creatorcontrib>Naim, Sue</creatorcontrib><creatorcontrib>Hao, Yong</creatorcontrib><creatorcontrib>Keer, Harold</creatorcontrib><creatorcontrib>Azab, Mohammad</creatorcontrib><creatorcontrib>Matei, Daniela</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oza, Amit M</au><au>Matulonis, Ursula A</au><au>Alvarez Secord, Angeles</au><au>Nemunaitis, John</au><au>Roman, Lynda D</au><au>Blagden, Sarah P</au><au>Banerjee, Susana</au><au>McGuire, William P</au><au>Ghamande, Sharad</au><au>Birrer, Michael J</au><au>Fleming, Gini F</au><au>Markham, Merry Jennifer</au><au>Hirte, Hal W</au><au>Provencher, Diane M</au><au>Basu, Bristi</au><au>Kristeleit, Rebecca</au><au>Armstrong, Deborah K</au><au>Schwartz, Benjamin</au><au>Braly, Patricia</au><au>Hall, Geoff D</au><au>Nephew, Kenneth P</au><au>Jueliger, Simone</au><au>Oganesian, Aram</au><au>Naim, Sue</au><au>Hao, Yong</au><au>Keer, Harold</au><au>Azab, Mohammad</au><au>Matei, Daniela</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>26</volume><issue>5</issue><spage>1009</spage><epage>1016</epage><pages>1009-1016</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer.
Patients received either G+C (guadecitabine 30 mg/m
s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS).
Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively;
= 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group;
= 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group.
Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.</abstract><cop>United States</cop><pmid>31831561</pmid><doi>10.1158/1078-0432.CCR-19-1638</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-8783-3491</orcidid><orcidid>https://orcid.org/0000-0002-8864-5932</orcidid><orcidid>https://orcid.org/0000-0003-2888-4146</orcidid><orcidid>https://orcid.org/0000-0003-3567-3494</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2020-03, Vol.26 (5), p.1009-1016 |
| issn | 1078-0432 1557-3265 |
| language | eng |
| recordid | cdi_crossref_primary_10_1158_1078_0432_CCR_19_1638 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols - therapeutic use Azacitidine - administration & dosage Azacitidine - analogs & derivatives Carboplatin - administration & dosage Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Doxorubicin - administration & dosage Doxorubicin - analogs & derivatives Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Epigenesis, Genetic - drug effects Female Humans Middle Aged Neoplasm Recurrence, Local - drug therapy Neoplasm Recurrence, Local - mortality Neoplasm Recurrence, Local - pathology Ovarian Neoplasms - drug therapy Ovarian Neoplasms - mortality Ovarian Neoplasms - pathology Paclitaxel - administration & dosage Patient Safety Polyethylene Glycols - administration & dosage Survival Rate Topotecan - administration & dosage Treatment Outcome |
| title | A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer |
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