A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer
High-grade serous ovarian cancer, the most frequent type of ovarian cancer, has a poor prognosis and novel treatments are needed for patients with platinum resistant/refractory disease. New therapeutic strategies targeting cell cycle checkpoints, including CHK1 inhibition with prexasertib, may help...
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| Veröffentlicht in: | Gynecologic oncology 2022-11, Vol.167 (2), p.213-225 |
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| creator | Konstantinopoulos, Panagiotis A. Lee, Jung-min Gao, Bo Miller, Rowan Lee, Jung-Yun Colombo, Nicoletta Vergote, Ignace Credille, Kelly M. Young, Suzanne R. McNeely, Samuel Wang, Xuejing Aimee Lin, Aimee Bence Shapira-Frommer, Ronnie |
| description | High-grade serous ovarian cancer, the most frequent type of ovarian cancer, has a poor prognosis and novel treatments are needed for patients with platinum resistant/refractory disease. New therapeutic strategies targeting cell cycle checkpoints, including CHK1 inhibition with prexasertib, may help improve clinical response and overcome resistance.
Patients with ovarian cancer (N = 169) were assigned to 4 cohorts as part of the Phase 2 multicenter trial (NCT03414047): Cohort 1: platinum resistant, BRCA-wildtype with ≥3 lines prior therapy; Cohort 2: platinum resistant BRCA-wildtype with |
| doi_str_mv | 10.1016/j.ygyno.2022.09.019 |
| format | Article |
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Patients with ovarian cancer (N = 169) were assigned to 4 cohorts as part of the Phase 2 multicenter trial (NCT03414047): Cohort 1: platinum resistant, BRCA-wildtype with ≥3 lines prior therapy; Cohort 2: platinum resistant BRCA-wildtype with <3 lines prior therapy; Cohort 3: platinum resistant, BRCA-mutated with prior PARP inhibitor therapy; Cohort 4: platinum refractory, BRCA-mutated, or BRCA-wildtype with any number of prior therapy lines. The primary endpoint was objective response rate (ORR) and secondary endpoints included disease control rate (DCR), and safety. DNA from tumor biopsies was sequenced to identify biomarkers.
The ORR in platinum resistant patients (Cohorts 1--3) was 12.1%, and 6.9% in platinum refractory patients. In platinum resistant patients, DCR was 37.1%, and consistent across cohorts. In platinum refractory patients, DCR was 31.0%. Consistent with the prexasertib mechanism of action, the most common treatment related adverse events of all grades included thrombocytopenia, neutropenia, fatigue, nausea, and anemia.
Prexasertib demonstrated durable single agent activity in a subset of patients with recurrent ovarian cancer regardless of clinical characteristics, BRCA status, or prior therapies, including PARPi. There was no obvious correlation with genomic alterations in responders vs non-responders, emphasizing the need for alternative biomarker approaches for responder identification.
•Prexasertib, a CHK1 inhibitor, was assessed in platinum resistant or platinum refractory HGSOC patients.•Prexasertib showed durable single agent activity in a subset of patients with recurrent HGSOC.•The most common treatment related adverse events included neutropenia, thrombocytopenia, fatigue, nausea, and anemia.•This study suggests the need to explore alternative approaches to identify predictive biomarkers for prexasertib response.</description><identifier>ISSN: 0090-8258</identifier><identifier>ISSN: 1095-6859</identifier><identifier>EISSN: 1095-6859</identifier><identifier>DOI: 10.1016/j.ygyno.2022.09.019</identifier><identifier>PMID: 36192237</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Carcinoma, Ovarian Epithelial - drug therapy ; Checkpoint kinase inhibitor ; Female ; Humans ; Neoplasm Recurrence, Local - drug therapy ; Neoplasm Recurrence, Local - genetics ; Neoplasm Recurrence, Local - pathology ; Ovarian cancer ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - pathology ; Platinum - therapeutic use ; Platinum refractory ; Platinum resistant ; Poly(ADP-ribose) Polymerase Inhibitors - adverse effects</subject><ispartof>Gynecologic oncology, 2022-11, Vol.167 (2), p.213-225</ispartof><rights>2022 The Authors</rights><rights>Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c460t-7ba3abf3b3b98bfeae5b08c6dc4ea19e7cad580e51e61e99297e6463949e7c573</citedby><cites>FETCH-LOGICAL-c460t-7ba3abf3b3b98bfeae5b08c6dc4ea19e7cad580e51e61e99297e6463949e7c573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ygyno.2022.09.019$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36192237$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Konstantinopoulos, Panagiotis A.</creatorcontrib><creatorcontrib>Lee, Jung-min</creatorcontrib><creatorcontrib>Gao, Bo</creatorcontrib><creatorcontrib>Miller, Rowan</creatorcontrib><creatorcontrib>Lee, Jung-Yun</creatorcontrib><creatorcontrib>Colombo, Nicoletta</creatorcontrib><creatorcontrib>Vergote, Ignace</creatorcontrib><creatorcontrib>Credille, Kelly M.</creatorcontrib><creatorcontrib>Young, Suzanne R.</creatorcontrib><creatorcontrib>McNeely, Samuel</creatorcontrib><creatorcontrib>Wang, Xuejing Aimee</creatorcontrib><creatorcontrib>Lin, Aimee Bence</creatorcontrib><creatorcontrib>Shapira-Frommer, Ronnie</creatorcontrib><title>A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer</title><title>Gynecologic oncology</title><addtitle>Gynecol Oncol</addtitle><description>High-grade serous ovarian cancer, the most frequent type of ovarian cancer, has a poor prognosis and novel treatments are needed for patients with platinum resistant/refractory disease. New therapeutic strategies targeting cell cycle checkpoints, including CHK1 inhibition with prexasertib, may help improve clinical response and overcome resistance.
Patients with ovarian cancer (N = 169) were assigned to 4 cohorts as part of the Phase 2 multicenter trial (NCT03414047): Cohort 1: platinum resistant, BRCA-wildtype with ≥3 lines prior therapy; Cohort 2: platinum resistant BRCA-wildtype with <3 lines prior therapy; Cohort 3: platinum resistant, BRCA-mutated with prior PARP inhibitor therapy; Cohort 4: platinum refractory, BRCA-mutated, or BRCA-wildtype with any number of prior therapy lines. The primary endpoint was objective response rate (ORR) and secondary endpoints included disease control rate (DCR), and safety. DNA from tumor biopsies was sequenced to identify biomarkers.
The ORR in platinum resistant patients (Cohorts 1--3) was 12.1%, and 6.9% in platinum refractory patients. In platinum resistant patients, DCR was 37.1%, and consistent across cohorts. In platinum refractory patients, DCR was 31.0%. Consistent with the prexasertib mechanism of action, the most common treatment related adverse events of all grades included thrombocytopenia, neutropenia, fatigue, nausea, and anemia.
Prexasertib demonstrated durable single agent activity in a subset of patients with recurrent ovarian cancer regardless of clinical characteristics, BRCA status, or prior therapies, including PARPi. There was no obvious correlation with genomic alterations in responders vs non-responders, emphasizing the need for alternative biomarker approaches for responder identification.
•Prexasertib, a CHK1 inhibitor, was assessed in platinum resistant or platinum refractory HGSOC patients.•Prexasertib showed durable single agent activity in a subset of patients with recurrent HGSOC.•The most common treatment related adverse events included neutropenia, thrombocytopenia, fatigue, nausea, and anemia.•This study suggests the need to explore alternative approaches to identify predictive biomarkers for prexasertib response.</description><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Carcinoma, Ovarian Epithelial - drug therapy</subject><subject>Checkpoint kinase inhibitor</subject><subject>Female</subject><subject>Humans</subject><subject>Neoplasm Recurrence, Local - drug therapy</subject><subject>Neoplasm Recurrence, Local - genetics</subject><subject>Neoplasm Recurrence, Local - pathology</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Platinum - therapeutic use</subject><subject>Platinum refractory</subject><subject>Platinum resistant</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - adverse effects</subject><issn>0090-8258</issn><issn>1095-6859</issn><issn>1095-6859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v1DAQtRCILoVfgIR8LIeEsb1x4gNCVcWXtBI9wIGT5TiTrVfZeLGdVfPv63RLRS-c5uvNm9F7hLxlUDJg8sOunLfz6EsOnJegSmDqGVkxUFUhm0o9JysABUXDq-aMvIpxBwACGH9JzoRkinNRr8j2kl7fmIiU05imbqa-p4eAt7kVkmvpxeY3lyCFbN5TN9LDYJIbpz0NGF1MZkzUh1z0wdjkw5xTO4WAS_9ogjMjtWa0GF6TF70ZIr55iOfk15fPP6--FZsfX79fXW4Ku5aQiro1wrS9aEWrmrZHg1ULjZWdXaNhCmtruqoBrBhKhkpxVaNcS6HWy6yqxTn5dOI9TO0eO5s_CWbQh-D2JszaG6efTkZ3o7f-qBnIWsh6Ybh4YAj-z4Qx6b2LFofBjOinqHnNGa-UEgtUnKA2-BizCo93GOjFI73T9x7pxSMNSmeP8ta7f1983PlrSgZ8PAEwC3V0GHS0DrOKncvyJt15998DdwvFpZs</recordid><startdate>20221101</startdate><enddate>20221101</enddate><creator>Konstantinopoulos, Panagiotis A.</creator><creator>Lee, Jung-min</creator><creator>Gao, Bo</creator><creator>Miller, Rowan</creator><creator>Lee, Jung-Yun</creator><creator>Colombo, Nicoletta</creator><creator>Vergote, Ignace</creator><creator>Credille, Kelly M.</creator><creator>Young, Suzanne R.</creator><creator>McNeely, Samuel</creator><creator>Wang, Xuejing Aimee</creator><creator>Lin, Aimee Bence</creator><creator>Shapira-Frommer, Ronnie</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20221101</creationdate><title>A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer</title><author>Konstantinopoulos, Panagiotis A. ; Lee, Jung-min ; Gao, Bo ; Miller, Rowan ; Lee, Jung-Yun ; Colombo, Nicoletta ; Vergote, Ignace ; Credille, Kelly M. ; Young, Suzanne R. ; McNeely, Samuel ; Wang, Xuejing Aimee ; Lin, Aimee Bence ; Shapira-Frommer, Ronnie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c460t-7ba3abf3b3b98bfeae5b08c6dc4ea19e7cad580e51e61e99297e6463949e7c573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Carcinoma, Ovarian Epithelial - drug therapy</topic><topic>Checkpoint kinase inhibitor</topic><topic>Female</topic><topic>Humans</topic><topic>Neoplasm Recurrence, Local - drug therapy</topic><topic>Neoplasm Recurrence, Local - genetics</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Platinum - therapeutic use</topic><topic>Platinum refractory</topic><topic>Platinum resistant</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - adverse effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Konstantinopoulos, Panagiotis A.</creatorcontrib><creatorcontrib>Lee, Jung-min</creatorcontrib><creatorcontrib>Gao, Bo</creatorcontrib><creatorcontrib>Miller, Rowan</creatorcontrib><creatorcontrib>Lee, Jung-Yun</creatorcontrib><creatorcontrib>Colombo, Nicoletta</creatorcontrib><creatorcontrib>Vergote, Ignace</creatorcontrib><creatorcontrib>Credille, Kelly M.</creatorcontrib><creatorcontrib>Young, Suzanne R.</creatorcontrib><creatorcontrib>McNeely, Samuel</creatorcontrib><creatorcontrib>Wang, Xuejing Aimee</creatorcontrib><creatorcontrib>Lin, Aimee Bence</creatorcontrib><creatorcontrib>Shapira-Frommer, Ronnie</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Gynecologic oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Konstantinopoulos, Panagiotis A.</au><au>Lee, Jung-min</au><au>Gao, Bo</au><au>Miller, Rowan</au><au>Lee, Jung-Yun</au><au>Colombo, Nicoletta</au><au>Vergote, Ignace</au><au>Credille, Kelly M.</au><au>Young, Suzanne R.</au><au>McNeely, Samuel</au><au>Wang, Xuejing Aimee</au><au>Lin, Aimee Bence</au><au>Shapira-Frommer, Ronnie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer</atitle><jtitle>Gynecologic oncology</jtitle><addtitle>Gynecol Oncol</addtitle><date>2022-11-01</date><risdate>2022</risdate><volume>167</volume><issue>2</issue><spage>213</spage><epage>225</epage><pages>213-225</pages><issn>0090-8258</issn><issn>1095-6859</issn><eissn>1095-6859</eissn><abstract>High-grade serous ovarian cancer, the most frequent type of ovarian cancer, has a poor prognosis and novel treatments are needed for patients with platinum resistant/refractory disease. New therapeutic strategies targeting cell cycle checkpoints, including CHK1 inhibition with prexasertib, may help improve clinical response and overcome resistance.
Patients with ovarian cancer (N = 169) were assigned to 4 cohorts as part of the Phase 2 multicenter trial (NCT03414047): Cohort 1: platinum resistant, BRCA-wildtype with ≥3 lines prior therapy; Cohort 2: platinum resistant BRCA-wildtype with <3 lines prior therapy; Cohort 3: platinum resistant, BRCA-mutated with prior PARP inhibitor therapy; Cohort 4: platinum refractory, BRCA-mutated, or BRCA-wildtype with any number of prior therapy lines. The primary endpoint was objective response rate (ORR) and secondary endpoints included disease control rate (DCR), and safety. DNA from tumor biopsies was sequenced to identify biomarkers.
The ORR in platinum resistant patients (Cohorts 1--3) was 12.1%, and 6.9% in platinum refractory patients. In platinum resistant patients, DCR was 37.1%, and consistent across cohorts. In platinum refractory patients, DCR was 31.0%. Consistent with the prexasertib mechanism of action, the most common treatment related adverse events of all grades included thrombocytopenia, neutropenia, fatigue, nausea, and anemia.
Prexasertib demonstrated durable single agent activity in a subset of patients with recurrent ovarian cancer regardless of clinical characteristics, BRCA status, or prior therapies, including PARPi. There was no obvious correlation with genomic alterations in responders vs non-responders, emphasizing the need for alternative biomarker approaches for responder identification.
•Prexasertib, a CHK1 inhibitor, was assessed in platinum resistant or platinum refractory HGSOC patients.•Prexasertib showed durable single agent activity in a subset of patients with recurrent HGSOC.•The most common treatment related adverse events included neutropenia, thrombocytopenia, fatigue, nausea, and anemia.•This study suggests the need to explore alternative approaches to identify predictive biomarkers for prexasertib response.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36192237</pmid><doi>10.1016/j.ygyno.2022.09.019</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Combined Chemotherapy Protocols - adverse effects Carcinoma, Ovarian Epithelial - drug therapy Checkpoint kinase inhibitor Female Humans Neoplasm Recurrence, Local - drug therapy Neoplasm Recurrence, Local - genetics Neoplasm Recurrence, Local - pathology Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Platinum - therapeutic use Platinum refractory Platinum resistant Poly(ADP-ribose) Polymerase Inhibitors - adverse effects |
| title | A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer |
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