SARC025 arms 1 and 2: A phase 1 study of the poly(ADP‐ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma
Background In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (N...
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| Veröffentlicht in: | Cancer 2021-04, Vol.127 (8), p.1301-1310 |
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| creator | Chugh, Rashmi Ballman, Karla V. Helman, Lee J. Patel, Shreyaskumar Whelan, Jeremy S. Widemann, Brigitte Lu, Yao Hawkins, Douglas S. Mascarenhas, Leo Glod, John W. Ji, Jiuping Zhang, Yiping Reinke, Denise Strauss, Sandra J. |
| description | Background
In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES.
Methods
Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2‐6 [D2‐6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re‐escalation in cohort C. In arm 2, patients were assigned to NIR (days 1‐7 [D1‐7]) and escalating doses of IRN (D2‐6).
Results
From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose‐limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1‐7 plus TMZ at 30 mg/m2 every day on D2‐6 (arm 1) or NIR at 100 mg every day on D1‐7 plus IRN at 20 mg/m2 every day on D2‐6 (arm 2). One confirmed partial response was observed in arm 2; the median progression‐free survival was 9.0 weeks (95% CI, 7.0‐10.1 weeks) and 16.3 weeks (95% CI, 5.1‐69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP‐ribose) activity was 89% (range, 83%‐98%).
Conclusions
The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple‐combination study of NIR, IRN, and TMZ has commenced.
Preclinical evaluations have identified the EWS‐FLI1 translocation, pathognomonic of Ewing sarcoma, as a predictive factor of response to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors with synergistic cell death in vivo with DNA damaging agents. This phase 1 study examines the dosing and safety of a combination of the PARP inhibitor niraparib with temozolomide or irinotecan. |
| doi_str_mv | 10.1002/cncr.33349 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8246769</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2468331088</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4489-d1e149b8778c2676369e652723656dfd83caf89676cfcaf25d78f281bdfe3c2b3</originalsourceid><addsrcrecordid>eNqNkstu1DAUhiMEokNhwwMgS2wKaIovudhdII1CuUgVoAISO8uxnY6rxA520tGw4hF4Ch6MJ-FMZxgBC8TK9jnf-fXbv7PsPsHHBGP6VHsdjxljubiRzQgW1RyTnN7MZhhjPi9y9ukgu5PSJRwrWrDb2QFjlAtB8Sz7_n5xXmNaIBX7hAhS3iB6ghZoWKpkoZDGyaxRaNG4tGgI3fpo8fzdj6_fomtCso-uS72NG9j5pWvcGCLyLqpBAYJWblyi0fbhS-hC74xF0HbR-TBarTzMoEGNzvoxbVllrpTX1qDTlfMXKKmoQ6_uZrda1SV7b7ceZh9fnH6oX83P3r58XS_O5jrPuZgbYkkuGl5VXNOyKlkpbFnQirKyKE1rONOq5QI6uoUdLUzFW8pJY1rLNG3YYfZsqztMTW-NBl9RdXKIrldxLYNy8s-Od0t5Ea4kpzmoChA42gnE8HmyaZS9S9p2nfI2TEkCxhkjmHNAH_6FXoYperiepAUpCCVlXgL1eEvpGFKKtt2bIVhu4peb-OV1_AA_-N3-Hv2VNwB8C6xsE9qk4eG13WPwQQpRCsI47DCp3QjRBF-HyY8w-uT_R4EmO9p1dv0Pz7J-U59v3f8EDYnd3g</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2515121646</pqid></control><display><type>article</type><title>SARC025 arms 1 and 2: A phase 1 study of the poly(ADP‐ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma</title><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Access via Wiley Online Library</source><source>Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>Wiley Online Library (Open Access Collection)</source><source>Alma/SFX Local Collection</source><creator>Chugh, Rashmi ; Ballman, Karla V. ; Helman, Lee J. ; Patel, Shreyaskumar ; Whelan, Jeremy S. ; Widemann, Brigitte ; Lu, Yao ; Hawkins, Douglas S. ; Mascarenhas, Leo ; Glod, John W. ; Ji, Jiuping ; Zhang, Yiping ; Reinke, Denise ; Strauss, Sandra J.</creator><creatorcontrib>Chugh, Rashmi ; Ballman, Karla V. ; Helman, Lee J. ; Patel, Shreyaskumar ; Whelan, Jeremy S. ; Widemann, Brigitte ; Lu, Yao ; Hawkins, Douglas S. ; Mascarenhas, Leo ; Glod, John W. ; Ji, Jiuping ; Zhang, Yiping ; Reinke, Denise ; Strauss, Sandra J.</creatorcontrib><description>Background
In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES.
Methods
Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2‐6 [D2‐6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re‐escalation in cohort C. In arm 2, patients were assigned to NIR (days 1‐7 [D1‐7]) and escalating doses of IRN (D2‐6).
Results
From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose‐limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1‐7 plus TMZ at 30 mg/m2 every day on D2‐6 (arm 1) or NIR at 100 mg every day on D1‐7 plus IRN at 20 mg/m2 every day on D2‐6 (arm 2). One confirmed partial response was observed in arm 2; the median progression‐free survival was 9.0 weeks (95% CI, 7.0‐10.1 weeks) and 16.3 weeks (95% CI, 5.1‐69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP‐ribose) activity was 89% (range, 83%‐98%).
Conclusions
The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple‐combination study of NIR, IRN, and TMZ has commenced.
Preclinical evaluations have identified the EWS‐FLI1 translocation, pathognomonic of Ewing sarcoma, as a predictive factor of response to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors with synergistic cell death in vivo with DNA damaging agents. This phase 1 study examines the dosing and safety of a combination of the PARP inhibitor niraparib with temozolomide or irinotecan.</description><identifier>ISSN: 0008-543X</identifier><identifier>EISSN: 1097-0142</identifier><identifier>DOI: 10.1002/cncr.33349</identifier><identifier>PMID: 33289920</identifier><language>eng</language><publisher>HOBOKEN: Wiley</publisher><subject>Adenosine ; Adenosine diphosphate ; Alanine ; Alanine transaminase ; Anorexia ; Colitis ; Cytotoxic agents ; Cytotoxicity ; Dosage ; Ewing sarcoma ; Ewing's sarcoma ; Ewings sarcoma ; Inhibitors ; Irinotecan ; Life Sciences & Biomedicine ; Neutropenia ; niraparib ; Oncology ; Original ; poly(adenosine diphosphate ribose) polymerase (PARP) inhibition ; Poly(ADP-ribose) polymerase ; Ribose ; Sarcoma ; Science & Technology ; Temozolomide ; Thrombocytopenia ; Toxicity</subject><ispartof>Cancer, 2021-04, Vol.127 (8), p.1301-1310</ispartof><rights>2020 The Authors. published by Wiley Periodicals LLC on behalf of American Cancer Society</rights><rights>2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by-nc/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>true</woscitedreferencessubscribed><woscitedreferencescount>21</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000596913800001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c4489-d1e149b8778c2676369e652723656dfd83caf89676cfcaf25d78f281bdfe3c2b3</citedby><cites>FETCH-LOGICAL-c4489-d1e149b8778c2676369e652723656dfd83caf89676cfcaf25d78f281bdfe3c2b3</cites><orcidid>0000-0003-3602-1375 ; 0000-0003-4379-0201 ; 0000-0001-8328-0260 ; 0000-0001-7790-0777</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcncr.33349$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcncr.33349$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,782,786,887,1419,1435,27931,27932,39265,45581,45582,46416,46840</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33289920$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chugh, Rashmi</creatorcontrib><creatorcontrib>Ballman, Karla V.</creatorcontrib><creatorcontrib>Helman, Lee J.</creatorcontrib><creatorcontrib>Patel, Shreyaskumar</creatorcontrib><creatorcontrib>Whelan, Jeremy S.</creatorcontrib><creatorcontrib>Widemann, Brigitte</creatorcontrib><creatorcontrib>Lu, Yao</creatorcontrib><creatorcontrib>Hawkins, Douglas S.</creatorcontrib><creatorcontrib>Mascarenhas, Leo</creatorcontrib><creatorcontrib>Glod, John W.</creatorcontrib><creatorcontrib>Ji, Jiuping</creatorcontrib><creatorcontrib>Zhang, Yiping</creatorcontrib><creatorcontrib>Reinke, Denise</creatorcontrib><creatorcontrib>Strauss, Sandra J.</creatorcontrib><title>SARC025 arms 1 and 2: A phase 1 study of the poly(ADP‐ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma</title><title>Cancer</title><addtitle>CANCER-AM CANCER SOC</addtitle><addtitle>Cancer</addtitle><description>Background
In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES.
Methods
Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2‐6 [D2‐6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re‐escalation in cohort C. In arm 2, patients were assigned to NIR (days 1‐7 [D1‐7]) and escalating doses of IRN (D2‐6).
Results
From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose‐limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1‐7 plus TMZ at 30 mg/m2 every day on D2‐6 (arm 1) or NIR at 100 mg every day on D1‐7 plus IRN at 20 mg/m2 every day on D2‐6 (arm 2). One confirmed partial response was observed in arm 2; the median progression‐free survival was 9.0 weeks (95% CI, 7.0‐10.1 weeks) and 16.3 weeks (95% CI, 5.1‐69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP‐ribose) activity was 89% (range, 83%‐98%).
Conclusions
The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple‐combination study of NIR, IRN, and TMZ has commenced.
Preclinical evaluations have identified the EWS‐FLI1 translocation, pathognomonic of Ewing sarcoma, as a predictive factor of response to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors with synergistic cell death in vivo with DNA damaging agents. This phase 1 study examines the dosing and safety of a combination of the PARP inhibitor niraparib with temozolomide or irinotecan.</description><subject>Adenosine</subject><subject>Adenosine diphosphate</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Anorexia</subject><subject>Colitis</subject><subject>Cytotoxic agents</subject><subject>Cytotoxicity</subject><subject>Dosage</subject><subject>Ewing sarcoma</subject><subject>Ewing's sarcoma</subject><subject>Ewings sarcoma</subject><subject>Inhibitors</subject><subject>Irinotecan</subject><subject>Life Sciences & Biomedicine</subject><subject>Neutropenia</subject><subject>niraparib</subject><subject>Oncology</subject><subject>Original</subject><subject>poly(adenosine diphosphate ribose) polymerase (PARP) inhibition</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Ribose</subject><subject>Sarcoma</subject><subject>Science & Technology</subject><subject>Temozolomide</subject><subject>Thrombocytopenia</subject><subject>Toxicity</subject><issn>0008-543X</issn><issn>1097-0142</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>HGBXW</sourceid><recordid>eNqNkstu1DAUhiMEokNhwwMgS2wKaIovudhdII1CuUgVoAISO8uxnY6rxA520tGw4hF4Ch6MJ-FMZxgBC8TK9jnf-fXbv7PsPsHHBGP6VHsdjxljubiRzQgW1RyTnN7MZhhjPi9y9ukgu5PSJRwrWrDb2QFjlAtB8Sz7_n5xXmNaIBX7hAhS3iB6ghZoWKpkoZDGyaxRaNG4tGgI3fpo8fzdj6_fomtCso-uS72NG9j5pWvcGCLyLqpBAYJWblyi0fbhS-hC74xF0HbR-TBarTzMoEGNzvoxbVllrpTX1qDTlfMXKKmoQ6_uZrda1SV7b7ceZh9fnH6oX83P3r58XS_O5jrPuZgbYkkuGl5VXNOyKlkpbFnQirKyKE1rONOq5QI6uoUdLUzFW8pJY1rLNG3YYfZsqztMTW-NBl9RdXKIrldxLYNy8s-Od0t5Ea4kpzmoChA42gnE8HmyaZS9S9p2nfI2TEkCxhkjmHNAH_6FXoYperiepAUpCCVlXgL1eEvpGFKKtt2bIVhu4peb-OV1_AA_-N3-Hv2VNwB8C6xsE9qk4eG13WPwQQpRCsI47DCp3QjRBF-HyY8w-uT_R4EmO9p1dv0Pz7J-U59v3f8EDYnd3g</recordid><startdate>20210415</startdate><enddate>20210415</enddate><creator>Chugh, Rashmi</creator><creator>Ballman, Karla V.</creator><creator>Helman, Lee J.</creator><creator>Patel, Shreyaskumar</creator><creator>Whelan, Jeremy S.</creator><creator>Widemann, Brigitte</creator><creator>Lu, Yao</creator><creator>Hawkins, Douglas S.</creator><creator>Mascarenhas, Leo</creator><creator>Glod, John W.</creator><creator>Ji, Jiuping</creator><creator>Zhang, Yiping</creator><creator>Reinke, Denise</creator><creator>Strauss, Sandra J.</creator><general>Wiley</general><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3602-1375</orcidid><orcidid>https://orcid.org/0000-0003-4379-0201</orcidid><orcidid>https://orcid.org/0000-0001-8328-0260</orcidid><orcidid>https://orcid.org/0000-0001-7790-0777</orcidid></search><sort><creationdate>20210415</creationdate><title>SARC025 arms 1 and 2: A phase 1 study of the poly(ADP‐ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma</title><author>Chugh, Rashmi ; Ballman, Karla V. ; Helman, Lee J. ; Patel, Shreyaskumar ; Whelan, Jeremy S. ; Widemann, Brigitte ; Lu, Yao ; Hawkins, Douglas S. ; Mascarenhas, Leo ; Glod, John W. ; Ji, Jiuping ; Zhang, Yiping ; Reinke, Denise ; Strauss, Sandra J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4489-d1e149b8778c2676369e652723656dfd83caf89676cfcaf25d78f281bdfe3c2b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenosine</topic><topic>Adenosine diphosphate</topic><topic>Alanine</topic><topic>Alanine transaminase</topic><topic>Anorexia</topic><topic>Colitis</topic><topic>Cytotoxic agents</topic><topic>Cytotoxicity</topic><topic>Dosage</topic><topic>Ewing sarcoma</topic><topic>Ewing's sarcoma</topic><topic>Ewings sarcoma</topic><topic>Inhibitors</topic><topic>Irinotecan</topic><topic>Life Sciences & Biomedicine</topic><topic>Neutropenia</topic><topic>niraparib</topic><topic>Oncology</topic><topic>Original</topic><topic>poly(adenosine diphosphate ribose) polymerase (PARP) inhibition</topic><topic>Poly(ADP-ribose) polymerase</topic><topic>Ribose</topic><topic>Sarcoma</topic><topic>Science & Technology</topic><topic>Temozolomide</topic><topic>Thrombocytopenia</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chugh, Rashmi</creatorcontrib><creatorcontrib>Ballman, Karla V.</creatorcontrib><creatorcontrib>Helman, Lee J.</creatorcontrib><creatorcontrib>Patel, Shreyaskumar</creatorcontrib><creatorcontrib>Whelan, Jeremy S.</creatorcontrib><creatorcontrib>Widemann, Brigitte</creatorcontrib><creatorcontrib>Lu, Yao</creatorcontrib><creatorcontrib>Hawkins, Douglas S.</creatorcontrib><creatorcontrib>Mascarenhas, Leo</creatorcontrib><creatorcontrib>Glod, John W.</creatorcontrib><creatorcontrib>Ji, Jiuping</creatorcontrib><creatorcontrib>Zhang, Yiping</creatorcontrib><creatorcontrib>Reinke, Denise</creatorcontrib><creatorcontrib>Strauss, Sandra J.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chugh, Rashmi</au><au>Ballman, Karla V.</au><au>Helman, Lee J.</au><au>Patel, Shreyaskumar</au><au>Whelan, Jeremy S.</au><au>Widemann, Brigitte</au><au>Lu, Yao</au><au>Hawkins, Douglas S.</au><au>Mascarenhas, Leo</au><au>Glod, John W.</au><au>Ji, Jiuping</au><au>Zhang, Yiping</au><au>Reinke, Denise</au><au>Strauss, Sandra J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SARC025 arms 1 and 2: A phase 1 study of the poly(ADP‐ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma</atitle><jtitle>Cancer</jtitle><stitle>CANCER-AM CANCER SOC</stitle><addtitle>Cancer</addtitle><date>2021-04-15</date><risdate>2021</risdate><volume>127</volume><issue>8</issue><spage>1301</spage><epage>1310</epage><pages>1301-1310</pages><issn>0008-543X</issn><eissn>1097-0142</eissn><abstract>Background
In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES.
Methods
Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2‐6 [D2‐6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re‐escalation in cohort C. In arm 2, patients were assigned to NIR (days 1‐7 [D1‐7]) and escalating doses of IRN (D2‐6).
Results
From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose‐limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1‐7 plus TMZ at 30 mg/m2 every day on D2‐6 (arm 1) or NIR at 100 mg every day on D1‐7 plus IRN at 20 mg/m2 every day on D2‐6 (arm 2). One confirmed partial response was observed in arm 2; the median progression‐free survival was 9.0 weeks (95% CI, 7.0‐10.1 weeks) and 16.3 weeks (95% CI, 5.1‐69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP‐ribose) activity was 89% (range, 83%‐98%).
Conclusions
The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple‐combination study of NIR, IRN, and TMZ has commenced.
Preclinical evaluations have identified the EWS‐FLI1 translocation, pathognomonic of Ewing sarcoma, as a predictive factor of response to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors with synergistic cell death in vivo with DNA damaging agents. This phase 1 study examines the dosing and safety of a combination of the PARP inhibitor niraparib with temozolomide or irinotecan.</abstract><cop>HOBOKEN</cop><pub>Wiley</pub><pmid>33289920</pmid><doi>10.1002/cncr.33349</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-3602-1375</orcidid><orcidid>https://orcid.org/0000-0003-4379-0201</orcidid><orcidid>https://orcid.org/0000-0001-8328-0260</orcidid><orcidid>https://orcid.org/0000-0001-7790-0777</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer, 2021-04, Vol.127 (8), p.1301-1310 |
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| language | eng |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Access via Wiley Online Library; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; Wiley Online Library (Open Access Collection); Alma/SFX Local Collection |
| subjects | Adenosine Adenosine diphosphate Alanine Alanine transaminase Anorexia Colitis Cytotoxic agents Cytotoxicity Dosage Ewing sarcoma Ewing's sarcoma Ewings sarcoma Inhibitors Irinotecan Life Sciences & Biomedicine Neutropenia niraparib Oncology Original poly(adenosine diphosphate ribose) polymerase (PARP) inhibition Poly(ADP-ribose) polymerase Ribose Sarcoma Science & Technology Temozolomide Thrombocytopenia Toxicity |
| title | SARC025 arms 1 and 2: A phase 1 study of the poly(ADP‐ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-04T04%3A48%3A37IST&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=SARC025%20arms%201%20and%202:%20A%20phase%201%20study%20of%20the%20poly(ADP%E2%80%90ribose)%20polymerase%20inhibitor%20niraparib%20with%20temozolomide%20or%20irinotecan%20in%20patients%20with%20advanced%20Ewing%20sarcoma&rft.jtitle=Cancer&rft.au=Chugh,%20Rashmi&rft.date=2021-04-15&rft.volume=127&rft.issue=8&rft.spage=1301&rft.epage=1310&rft.pages=1301-1310&rft.issn=0008-543X&rft.eissn=1097-0142&rft_id=info:doi/10.1002/cncr.33349&rft_dat=%3Cproquest_pubme%3E2468331088%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=2515121646&rft_id=info:pmid/33289920&rfr_iscdi=true |