Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma
Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC. Patients were given p...
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| Veröffentlicht in: | Clinical cancer research 2018-07, Vol.24 (14), p.3263-3272 |
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| creator | Hong, David S Moore, Kathleen Patel, Manish Grant, Stefan C Burris, 3rd, Howard A William, Jr, William N Jones, Suzanne Meric-Bernstam, Funda Infante, Jeffrey Golden, Lisa Zhang, Wei Martinez, Ricardo Wijayawardana, Sameera Beckmann, Richard Lin, Aimee Bence Eng, Cathy Bendell, Johanna |
| description | Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC.
Patients were given prexasertib 105 mg/m
as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.
Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 1.4-3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.
Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m
was confirmed as the recommended phase II dose.
. |
| doi_str_mv | 10.1158/1078-0432.CCR-17-3347 |
| format | Article |
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Patients were given prexasertib 105 mg/m
as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.
Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 1.4-3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.
Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m
was confirmed as the recommended phase II dose.
.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-17-3347</identifier><identifier>PMID: 29643063</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>Adult ; Aged ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - therapeutic use ; Anus ; Biomarkers ; Cancer ; Carcinoma, Squamous Cell - diagnosis ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - mortality ; Checkpoint Kinase 1 - antagonists & inhibitors ; Checkpoint Kinase 1 - genetics ; Combined Modality Therapy ; Confidence intervals ; Deoxyribonucleic acid ; DNA ; DNA damage ; Enzyme inhibitors ; Female ; Gene Expression Profiling ; Head ; Humans ; Inhibitors ; Kaplan-Meier Estimate ; Lung cancer ; Male ; Middle Aged ; Neck ; Neoplasm Metastasis ; Neoplasm Staging ; Neutropenia ; Patients ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - adverse effects ; Protein Kinase Inhibitors - therapeutic use ; Pyrazines - administration & dosage ; Pyrazines - adverse effects ; Pyrazines - therapeutic use ; Pyrazoles - administration & dosage ; Pyrazoles - adverse effects ; Pyrazoles - therapeutic use ; Retreatment ; Safety ; Squamous cell carcinoma ; Treatment Outcome ; Tumors</subject><ispartof>Clinical cancer research, 2018-07, Vol.24 (14), p.3263-3272</ispartof><rights>2018 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc Jul 15, 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-44b37f6fe6cae7fa3979f69200215eddc3fa74e4afb2aeec36d4dc661f923c723</citedby><cites>FETCH-LOGICAL-c439t-44b37f6fe6cae7fa3979f69200215eddc3fa74e4afb2aeec36d4dc661f923c723</cites><orcidid>0000-0001-5008-8854</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29643063$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hong, David S</creatorcontrib><creatorcontrib>Moore, Kathleen</creatorcontrib><creatorcontrib>Patel, Manish</creatorcontrib><creatorcontrib>Grant, Stefan C</creatorcontrib><creatorcontrib>Burris, 3rd, Howard A</creatorcontrib><creatorcontrib>William, Jr, William N</creatorcontrib><creatorcontrib>Jones, Suzanne</creatorcontrib><creatorcontrib>Meric-Bernstam, Funda</creatorcontrib><creatorcontrib>Infante, Jeffrey</creatorcontrib><creatorcontrib>Golden, Lisa</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Martinez, Ricardo</creatorcontrib><creatorcontrib>Wijayawardana, Sameera</creatorcontrib><creatorcontrib>Beckmann, Richard</creatorcontrib><creatorcontrib>Lin, Aimee Bence</creatorcontrib><creatorcontrib>Eng, Cathy</creatorcontrib><creatorcontrib>Bendell, Johanna</creatorcontrib><title>Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC.
Patients were given prexasertib 105 mg/m
as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.
Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 1.4-3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.
Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m
was confirmed as the recommended phase II dose.
.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Anus</subject><subject>Biomarkers</subject><subject>Cancer</subject><subject>Carcinoma, Squamous Cell - diagnosis</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - mortality</subject><subject>Checkpoint Kinase 1 - antagonists & inhibitors</subject><subject>Checkpoint Kinase 1 - genetics</subject><subject>Combined Modality Therapy</subject><subject>Confidence intervals</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>Enzyme inhibitors</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Head</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Kaplan-Meier Estimate</subject><subject>Lung cancer</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neck</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Staging</subject><subject>Neutropenia</subject><subject>Patients</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - adverse effects</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Pyrazines - administration & dosage</subject><subject>Pyrazines - adverse effects</subject><subject>Pyrazines - therapeutic use</subject><subject>Pyrazoles - administration & dosage</subject><subject>Pyrazoles - adverse effects</subject><subject>Pyrazoles - therapeutic use</subject><subject>Retreatment</subject><subject>Safety</subject><subject>Squamous cell carcinoma</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkctu1jAQhS0Eohd4BJAlNiya1rfYyQYJRQV-tVIrCmvLcWzikth_bae0b1-nNwGrGc18czRHB4B3GB1iXDdHGImmQoySw677XmFRUcrEC7CL67r0hNcvS__E7IC9lC4Rwgwj9hrskJYzijjdBTfH12paVHbBw2DheTQ3KpmYXX8AFexGo39vg_MZnjhfFhDDjR9d73KIB9D5wpyP63zTw4u8DLf3IkXO-JzgH5dHeHG1qDksCXZmmmCnonY-zOoNeGXVlMzbx7oPfn45_tF9q07Pvm66z6eVZrTNFWM9FZZbw7UywiraitbyliBEcG2GQVOrBDNM2Z4oYzTlAxs059i2hGpB6D749KC7XfrZDLo8FtUkt9HNKt7KoJz8d-PdKH-Fa8lRjVDDi8DHR4EYrhaTspxd0sWL8qbYkgQRxkTdNk1BP_yHXoYl-mKvUAIhxgtWqPqB0jGkFI19fgYjuWYr19zkmpss2Uos5JptuXv_t5Pnq6cw6R2oQKEF</recordid><startdate>20180715</startdate><enddate>20180715</enddate><creator>Hong, David S</creator><creator>Moore, Kathleen</creator><creator>Patel, Manish</creator><creator>Grant, Stefan C</creator><creator>Burris, 3rd, Howard A</creator><creator>William, Jr, William N</creator><creator>Jones, Suzanne</creator><creator>Meric-Bernstam, Funda</creator><creator>Infante, Jeffrey</creator><creator>Golden, Lisa</creator><creator>Zhang, Wei</creator><creator>Martinez, Ricardo</creator><creator>Wijayawardana, Sameera</creator><creator>Beckmann, Richard</creator><creator>Lin, Aimee Bence</creator><creator>Eng, Cathy</creator><creator>Bendell, Johanna</creator><general>American Association for Cancer Research Inc</general><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>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5008-8854</orcidid></search><sort><creationdate>20180715</creationdate><title>Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma</title><author>Hong, David S ; Moore, Kathleen ; Patel, Manish ; Grant, Stefan C ; Burris, 3rd, Howard A ; William, Jr, William N ; Jones, Suzanne ; Meric-Bernstam, Funda ; Infante, Jeffrey ; Golden, Lisa ; Zhang, Wei ; Martinez, Ricardo ; Wijayawardana, Sameera ; Beckmann, Richard ; Lin, Aimee Bence ; Eng, Cathy ; Bendell, Johanna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-44b37f6fe6cae7fa3979f69200215eddc3fa74e4afb2aeec36d4dc661f923c723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Anus</topic><topic>Biomarkers</topic><topic>Cancer</topic><topic>Carcinoma, Squamous Cell - diagnosis</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Carcinoma, Squamous Cell - genetics</topic><topic>Carcinoma, Squamous Cell - mortality</topic><topic>Checkpoint Kinase 1 - antagonists & inhibitors</topic><topic>Checkpoint Kinase 1 - genetics</topic><topic>Combined Modality Therapy</topic><topic>Confidence intervals</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>Enzyme inhibitors</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Head</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Kaplan-Meier Estimate</topic><topic>Lung cancer</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neck</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Staging</topic><topic>Neutropenia</topic><topic>Patients</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - adverse effects</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Pyrazines - administration & dosage</topic><topic>Pyrazines - adverse effects</topic><topic>Pyrazines - therapeutic use</topic><topic>Pyrazoles - administration & dosage</topic><topic>Pyrazoles - adverse effects</topic><topic>Pyrazoles - therapeutic use</topic><topic>Retreatment</topic><topic>Safety</topic><topic>Squamous cell carcinoma</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hong, David S</creatorcontrib><creatorcontrib>Moore, Kathleen</creatorcontrib><creatorcontrib>Patel, Manish</creatorcontrib><creatorcontrib>Grant, Stefan C</creatorcontrib><creatorcontrib>Burris, 3rd, Howard A</creatorcontrib><creatorcontrib>William, Jr, William N</creatorcontrib><creatorcontrib>Jones, Suzanne</creatorcontrib><creatorcontrib>Meric-Bernstam, Funda</creatorcontrib><creatorcontrib>Infante, Jeffrey</creatorcontrib><creatorcontrib>Golden, Lisa</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Martinez, Ricardo</creatorcontrib><creatorcontrib>Wijayawardana, Sameera</creatorcontrib><creatorcontrib>Beckmann, Richard</creatorcontrib><creatorcontrib>Lin, Aimee Bence</creatorcontrib><creatorcontrib>Eng, Cathy</creatorcontrib><creatorcontrib>Bendell, Johanna</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hong, David S</au><au>Moore, Kathleen</au><au>Patel, Manish</au><au>Grant, Stefan C</au><au>Burris, 3rd, Howard A</au><au>William, Jr, William N</au><au>Jones, Suzanne</au><au>Meric-Bernstam, Funda</au><au>Infante, Jeffrey</au><au>Golden, Lisa</au><au>Zhang, Wei</au><au>Martinez, Ricardo</au><au>Wijayawardana, Sameera</au><au>Beckmann, Richard</au><au>Lin, Aimee Bence</au><au>Eng, Cathy</au><au>Bendell, Johanna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2018-07-15</date><risdate>2018</risdate><volume>24</volume><issue>14</issue><spage>3263</spage><epage>3272</epage><pages>3263-3272</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC.
Patients were given prexasertib 105 mg/m
as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.
Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 1.4-3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.
Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m
was confirmed as the recommended phase II dose.
.</abstract><cop>United States</cop><pub>American Association for Cancer Research Inc</pub><pmid>29643063</pmid><doi>10.1158/1078-0432.CCR-17-3347</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-5008-8854</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2018-07, Vol.24 (14), p.3263-3272 |
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| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | Adult Aged Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Anus Biomarkers Cancer Carcinoma, Squamous Cell - diagnosis Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - mortality Checkpoint Kinase 1 - antagonists & inhibitors Checkpoint Kinase 1 - genetics Combined Modality Therapy Confidence intervals Deoxyribonucleic acid DNA DNA damage Enzyme inhibitors Female Gene Expression Profiling Head Humans Inhibitors Kaplan-Meier Estimate Lung cancer Male Middle Aged Neck Neoplasm Metastasis Neoplasm Staging Neutropenia Patients Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - adverse effects Protein Kinase Inhibitors - therapeutic use Pyrazines - administration & dosage Pyrazines - adverse effects Pyrazines - therapeutic use Pyrazoles - administration & dosage Pyrazoles - adverse effects Pyrazoles - therapeutic use Retreatment Safety Squamous cell carcinoma Treatment Outcome Tumors |
| title | Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma |
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