Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study
Background The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in p...
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| Veröffentlicht in: | British journal of cancer 2020-04, Vol.122 (8), p.1158-1165 |
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| creator | Gelderblom, Hans Jones, Robin L. George, Suzanne Valverde Morales, Claudia Benson, Charlotte Jean-Yves Blay Renouf, Daniel J. Doi, Toshihiko Le Cesne, Axel Leahy, Michael Hertle, Sabine Aimone, Paola Brandt, Ulrike Schӧffski, Patrick |
| description | Background
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.
Methods
This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.
Results
Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.
Conclusions
Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.
Trial registration number
NCT01468688. |
| doi_str_mv | 10.1038/s41416-020-0769-y |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7156686</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2389687331</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-6621495a4afd3f69183fa9e1c7fbc5faa1d4d1ee337682da7348f77cfd841b833</originalsourceid><addsrcrecordid>eNp1Uk-P1SAQJ0bjPlc_gBdD4tUqlD6gHkw2G_9ssoke9ExogVfWFipQN_2QfifnbXdXPXggk2F-f4ZhEHpOyWtKmHyTG9pQXpGaVETwtlofoB3ds7qishYP0Y4QIirS1uQEPcn5CtKWSPEYnbCaNoILukO_LiZdfPAd9gH3cep8gDwGfO3LgOchZjg-xOxLHPF3qGYL0MF3cJFwt8w6jT5v_BmoNpS8kQ86lwTcYjM46BEf0wliWaa4JHw9ROy0H63Bc_IgVgab9LxubH_Xlw4G5yX4m-wt1vjLcOyBdq_wtIzF9-CYLIgvZn2KHjk9ZvvsNp6ibx_efz3_VF1-_nhxfnZZ9Y0gpeIc3t_udaOdYY63VDKnW0t74bp-77SmpjHUWsYEl7XRgjXSCdE7IxvaScZO0btNd166yZqbFvSo4BmTTquK2qt_K8EP6hB_KkH3nEsOAi9vBVL8scCA1BWMBIaUVc1ky6VgjAKKbqg-xZyTdfcOlKjjBqhtAxRsgDpugFqB8-Lv1u4Zd18OgHoDZCiFg01_rP-v-hvKwsT8</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2389687331</pqid></control><display><type>article</type><title>Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study</title><source>MEDLINE</source><source>SpringerLink Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Gelderblom, Hans ; Jones, Robin L. ; George, Suzanne ; Valverde Morales, Claudia ; Benson, Charlotte ; Jean-Yves Blay ; Renouf, Daniel J. ; Doi, Toshihiko ; Le Cesne, Axel ; Leahy, Michael ; Hertle, Sabine ; Aimone, Paola ; Brandt, Ulrike ; Schӧffski, Patrick</creator><creatorcontrib>Gelderblom, Hans ; Jones, Robin L. ; George, Suzanne ; Valverde Morales, Claudia ; Benson, Charlotte ; Jean-Yves Blay ; Renouf, Daniel J. ; Doi, Toshihiko ; Le Cesne, Axel ; Leahy, Michael ; Hertle, Sabine ; Aimone, Paola ; Brandt, Ulrike ; Schӧffski, Patrick</creatorcontrib><description>Background
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.
Methods
This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.
Results
Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.
Conclusions
Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.
Trial registration number
NCT01468688.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/s41416-020-0769-y</identifier><identifier>PMID: 32147671</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; 692/4028/67/1504/1829 ; 692/699/1503/1504/1829 ; Adult ; Aged ; Aminopyridines - administration & dosage ; Aminopyridines - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Drug Resistance ; Enzyme inhibitors ; Epidemiology ; Female ; Gastrointestinal cancer ; Gastrointestinal Neoplasms - drug therapy ; Gastrointestinal Neoplasms - mortality ; Gastrointestinal Stromal Tumors - drug therapy ; Gastrointestinal Stromal Tumors - mortality ; Humans ; Imatinib ; Imatinib Mesylate - administration & dosage ; Imatinib Mesylate - adverse effects ; Inhibitor drugs ; Male ; Mental Disorders - chemically induced ; Metastases ; Middle Aged ; Molecular Medicine ; Morpholines - administration & dosage ; Morpholines - adverse effects ; Oncology ; Patients ; Phosphoinositide-3 Kinase Inhibitors - administration & dosage ; Sunitinib - administration & dosage ; Targeted cancer therapy ; Tumors</subject><ispartof>British journal of cancer, 2020-04, Vol.122 (8), p.1158-1165</ispartof><rights>The Author(s), under exclusive licence to Cancer Research UK 2020</rights><rights>The Author(s), under exclusive licence to Cancer Research UK 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-6621495a4afd3f69183fa9e1c7fbc5faa1d4d1ee337682da7348f77cfd841b833</citedby><cites>FETCH-LOGICAL-c470t-6621495a4afd3f69183fa9e1c7fbc5faa1d4d1ee337682da7348f77cfd841b833</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156686/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156686/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32147671$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gelderblom, Hans</creatorcontrib><creatorcontrib>Jones, Robin L.</creatorcontrib><creatorcontrib>George, Suzanne</creatorcontrib><creatorcontrib>Valverde Morales, Claudia</creatorcontrib><creatorcontrib>Benson, Charlotte</creatorcontrib><creatorcontrib>Jean-Yves Blay</creatorcontrib><creatorcontrib>Renouf, Daniel J.</creatorcontrib><creatorcontrib>Doi, Toshihiko</creatorcontrib><creatorcontrib>Le Cesne, Axel</creatorcontrib><creatorcontrib>Leahy, Michael</creatorcontrib><creatorcontrib>Hertle, Sabine</creatorcontrib><creatorcontrib>Aimone, Paola</creatorcontrib><creatorcontrib>Brandt, Ulrike</creatorcontrib><creatorcontrib>Schӧffski, Patrick</creatorcontrib><title>Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.
Methods
This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.
Results
Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.
Conclusions
Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.
Trial registration number
NCT01468688.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>692/4028/67/1504/1829</subject><subject>692/699/1503/1504/1829</subject><subject>Adult</subject><subject>Aged</subject><subject>Aminopyridines - administration & dosage</subject><subject>Aminopyridines - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Drug Resistance</subject><subject>Enzyme inhibitors</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Gastrointestinal cancer</subject><subject>Gastrointestinal Neoplasms - drug therapy</subject><subject>Gastrointestinal Neoplasms - mortality</subject><subject>Gastrointestinal Stromal Tumors - drug therapy</subject><subject>Gastrointestinal Stromal Tumors - mortality</subject><subject>Humans</subject><subject>Imatinib</subject><subject>Imatinib Mesylate - administration & dosage</subject><subject>Imatinib Mesylate - adverse effects</subject><subject>Inhibitor drugs</subject><subject>Male</subject><subject>Mental Disorders - chemically induced</subject><subject>Metastases</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Morpholines - administration & dosage</subject><subject>Morpholines - adverse effects</subject><subject>Oncology</subject><subject>Patients</subject><subject>Phosphoinositide-3 Kinase Inhibitors - administration & dosage</subject><subject>Sunitinib - administration & dosage</subject><subject>Targeted cancer therapy</subject><subject>Tumors</subject><issn>0007-0920</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1Uk-P1SAQJ0bjPlc_gBdD4tUqlD6gHkw2G_9ssoke9ExogVfWFipQN_2QfifnbXdXPXggk2F-f4ZhEHpOyWtKmHyTG9pQXpGaVETwtlofoB3ds7qishYP0Y4QIirS1uQEPcn5CtKWSPEYnbCaNoILukO_LiZdfPAd9gH3cep8gDwGfO3LgOchZjg-xOxLHPF3qGYL0MF3cJFwt8w6jT5v_BmoNpS8kQ86lwTcYjM46BEf0wliWaa4JHw9ROy0H63Bc_IgVgab9LxubH_Xlw4G5yX4m-wt1vjLcOyBdq_wtIzF9-CYLIgvZn2KHjk9ZvvsNp6ibx_efz3_VF1-_nhxfnZZ9Y0gpeIc3t_udaOdYY63VDKnW0t74bp-77SmpjHUWsYEl7XRgjXSCdE7IxvaScZO0btNd166yZqbFvSo4BmTTquK2qt_K8EP6hB_KkH3nEsOAi9vBVL8scCA1BWMBIaUVc1ky6VgjAKKbqg-xZyTdfcOlKjjBqhtAxRsgDpugFqB8-Lv1u4Zd18OgHoDZCiFg01_rP-v-hvKwsT8</recordid><startdate>20200401</startdate><enddate>20200401</enddate><creator>Gelderblom, Hans</creator><creator>Jones, Robin L.</creator><creator>George, Suzanne</creator><creator>Valverde Morales, Claudia</creator><creator>Benson, Charlotte</creator><creator>Jean-Yves Blay</creator><creator>Renouf, Daniel J.</creator><creator>Doi, Toshihiko</creator><creator>Le Cesne, Axel</creator><creator>Leahy, Michael</creator><creator>Hertle, Sabine</creator><creator>Aimone, Paola</creator><creator>Brandt, Ulrike</creator><creator>Schӧffski, Patrick</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20200401</creationdate><title>Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study</title><author>Gelderblom, Hans ; Jones, Robin L. ; George, Suzanne ; Valverde Morales, Claudia ; Benson, Charlotte ; Jean-Yves Blay ; Renouf, Daniel J. ; Doi, Toshihiko ; Le Cesne, Axel ; Leahy, Michael ; Hertle, Sabine ; Aimone, Paola ; Brandt, Ulrike ; Schӧffski, Patrick</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-6621495a4afd3f69183fa9e1c7fbc5faa1d4d1ee337682da7348f77cfd841b833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>692/4028/67/1504/1829</topic><topic>692/699/1503/1504/1829</topic><topic>Adult</topic><topic>Aged</topic><topic>Aminopyridines - administration & dosage</topic><topic>Aminopyridines - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Drug Resistance</topic><topic>Enzyme inhibitors</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Gastrointestinal cancer</topic><topic>Gastrointestinal Neoplasms - drug therapy</topic><topic>Gastrointestinal Neoplasms - mortality</topic><topic>Gastrointestinal Stromal Tumors - drug therapy</topic><topic>Gastrointestinal Stromal Tumors - mortality</topic><topic>Humans</topic><topic>Imatinib</topic><topic>Imatinib Mesylate - administration & dosage</topic><topic>Imatinib Mesylate - adverse effects</topic><topic>Inhibitor drugs</topic><topic>Male</topic><topic>Mental Disorders - chemically induced</topic><topic>Metastases</topic><topic>Middle Aged</topic><topic>Molecular Medicine</topic><topic>Morpholines - administration & dosage</topic><topic>Morpholines - adverse effects</topic><topic>Oncology</topic><topic>Patients</topic><topic>Phosphoinositide-3 Kinase Inhibitors - administration & dosage</topic><topic>Sunitinib - administration & dosage</topic><topic>Targeted cancer therapy</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gelderblom, Hans</creatorcontrib><creatorcontrib>Jones, Robin L.</creatorcontrib><creatorcontrib>George, Suzanne</creatorcontrib><creatorcontrib>Valverde Morales, Claudia</creatorcontrib><creatorcontrib>Benson, Charlotte</creatorcontrib><creatorcontrib>Jean-Yves Blay</creatorcontrib><creatorcontrib>Renouf, Daniel J.</creatorcontrib><creatorcontrib>Doi, Toshihiko</creatorcontrib><creatorcontrib>Le Cesne, Axel</creatorcontrib><creatorcontrib>Leahy, Michael</creatorcontrib><creatorcontrib>Hertle, Sabine</creatorcontrib><creatorcontrib>Aimone, Paola</creatorcontrib><creatorcontrib>Brandt, Ulrike</creatorcontrib><creatorcontrib>Schӧffski, Patrick</creatorcontrib><collection>Springer Nature OA Free Journals</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>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</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 China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gelderblom, Hans</au><au>Jones, Robin L.</au><au>George, Suzanne</au><au>Valverde Morales, Claudia</au><au>Benson, Charlotte</au><au>Jean-Yves Blay</au><au>Renouf, Daniel J.</au><au>Doi, Toshihiko</au><au>Le Cesne, Axel</au><au>Leahy, Michael</au><au>Hertle, Sabine</au><au>Aimone, Paola</au><au>Brandt, Ulrike</au><au>Schӧffski, Patrick</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2020-04-01</date><risdate>2020</risdate><volume>122</volume><issue>8</issue><spage>1158</spage><epage>1165</epage><pages>1158-1165</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><abstract>Background
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.
Methods
This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.
Results
Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.
Conclusions
Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.
Trial registration number
NCT01468688.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32147671</pmid><doi>10.1038/s41416-020-0769-y</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | British journal of cancer, 2020-04, Vol.122 (8), p.1158-1165 |
| issn | 0007-0920 1532-1827 |
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| source | MEDLINE; SpringerLink Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | 1-Phosphatidylinositol 3-kinase 692/4028/67/1504/1829 692/699/1503/1504/1829 Adult Aged Aminopyridines - administration & dosage Aminopyridines - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biomedical and Life Sciences Biomedicine Cancer Research Drug Resistance Enzyme inhibitors Epidemiology Female Gastrointestinal cancer Gastrointestinal Neoplasms - drug therapy Gastrointestinal Neoplasms - mortality Gastrointestinal Stromal Tumors - drug therapy Gastrointestinal Stromal Tumors - mortality Humans Imatinib Imatinib Mesylate - administration & dosage Imatinib Mesylate - adverse effects Inhibitor drugs Male Mental Disorders - chemically induced Metastases Middle Aged Molecular Medicine Morpholines - administration & dosage Morpholines - adverse effects Oncology Patients Phosphoinositide-3 Kinase Inhibitors - administration & dosage Sunitinib - administration & dosage Targeted cancer therapy Tumors |
| title | Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study |
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