A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors
Background: Imatinib is standard therapy for advanced gastrointestinal stromal tumors (GIST), but most patients develop resistance. This phase I–II study assessed the safety and efficacy of coadministering everolimus with imatinib in imatinib-resistant GIST. Patients and methods: In phase I, patient...
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| Veröffentlicht in: | Annals of oncology 2010-10, Vol.21 (10), p.1990-1998 |
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| container_end_page | 1998 |
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| container_issue | 10 |
| container_start_page | 1990 |
| container_title | Annals of oncology |
| container_volume | 21 |
| creator | Schöffski, P. Reichardt, P. Blay, J.-Y. Dumez, H. Morgan, J.A. Ray-Coquard, I. Hollaender, N. Jappe, A. Demetri, G.D. |
| description | Background: Imatinib is standard therapy for advanced gastrointestinal stromal tumors (GIST), but most patients develop resistance. This phase I–II study assessed the safety and efficacy of coadministering everolimus with imatinib in imatinib-resistant GIST.
Patients and methods: In phase I, patients received imatinib (600/800mg/day) combined with weekly (20mg) or daily (2.5/5.0mg) everolimus to determine the optimal dose. In phase II, patients were divided into two strata (progression on imatinib only; progression after imatinib and sunitinib/other tyrosine kinase inhibitor) and received everolimus 2.5mg plus imatinib 600mg/day. Primary end point was 4-month progression-free survival (PFS).
Results: Combination treatment was well tolerated. Common adverse events were diarrhea, nausea, fatigue, and anemia. In phase II strata 1 and 2, 4 of 23 (17%) and 13 of 35 (37%) assessable patients, respectively, were progression free at 4 months; median PFS was 1.9 and 3.5 months, and median overall survival was 14.9 and 10.7 months, respectively. In stratum 1, 36% had stable disease (SD) and 54% progressive disease (PD), while in stratum 2, 2% had partial response, 43% SD, and 32% PD.
Conclusion: Predetermined efficacy criteria were met in both strata. The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST. |
| doi_str_mv | 10.1093/annonc/mdq076 |
| format | Article |
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Patients and methods: In phase I, patients received imatinib (600/800mg/day) combined with weekly (20mg) or daily (2.5/5.0mg) everolimus to determine the optimal dose. In phase II, patients were divided into two strata (progression on imatinib only; progression after imatinib and sunitinib/other tyrosine kinase inhibitor) and received everolimus 2.5mg plus imatinib 600mg/day. Primary end point was 4-month progression-free survival (PFS).
Results: Combination treatment was well tolerated. Common adverse events were diarrhea, nausea, fatigue, and anemia. In phase II strata 1 and 2, 4 of 23 (17%) and 13 of 35 (37%) assessable patients, respectively, were progression free at 4 months; median PFS was 1.9 and 3.5 months, and median overall survival was 14.9 and 10.7 months, respectively. In stratum 1, 36% had stable disease (SD) and 54% progressive disease (PD), while in stratum 2, 2% had partial response, 43% SD, and 32% PD.
Conclusion: Predetermined efficacy criteria were met in both strata. The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST.</description><identifier>ISSN: 0923-7534</identifier><identifier>EISSN: 1569-8041</identifier><identifier>DOI: 10.1093/annonc/mdq076</identifier><identifier>PMID: 20507881</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Antineoplastic agents ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Benzamides ; Biological and medical sciences ; Drug Resistance, Neoplasm ; Everolimus ; everolimus (RAD001) ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; gastrointestinal stromal tumors ; Gastrointestinal Stromal Tumors - drug therapy ; Gastrointestinal Stromal Tumors - pathology ; GIST ; Humans ; imatinib ; Imatinib Mesylate ; Male ; Medical sciences ; Middle Aged ; Neoplasm Recurrence, Local - drug therapy ; Neoplasm Recurrence, Local - pathology ; Neoplasm Staging ; Pharmacology. Drug treatments ; Piperazines - administration & dosage ; Pyrimidines - administration & dosage ; Salvage Therapy ; Sirolimus - administration & dosage ; Sirolimus - analogs & derivatives ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Survival Rate ; Treatment Outcome ; Tumors</subject><ispartof>Annals of oncology, 2010-10, Vol.21 (10), p.1990-1998</ispartof><rights>2010 European Society for Medical Oncology</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-d92ddbad3b3f81dfdd7b51e8e2f721f3c8fcabe52b35661c1b957b59b00ffcd13</citedby><cites>FETCH-LOGICAL-c447t-d92ddbad3b3f81dfdd7b51e8e2f721f3c8fcabe52b35661c1b957b59b00ffcd13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23303022$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20507881$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schöffski, P.</creatorcontrib><creatorcontrib>Reichardt, P.</creatorcontrib><creatorcontrib>Blay, J.-Y.</creatorcontrib><creatorcontrib>Dumez, H.</creatorcontrib><creatorcontrib>Morgan, J.A.</creatorcontrib><creatorcontrib>Ray-Coquard, I.</creatorcontrib><creatorcontrib>Hollaender, N.</creatorcontrib><creatorcontrib>Jappe, A.</creatorcontrib><creatorcontrib>Demetri, G.D.</creatorcontrib><title>A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors</title><title>Annals of oncology</title><addtitle>Ann Oncol</addtitle><description>Background: Imatinib is standard therapy for advanced gastrointestinal stromal tumors (GIST), but most patients develop resistance. This phase I–II study assessed the safety and efficacy of coadministering everolimus with imatinib in imatinib-resistant GIST.
Patients and methods: In phase I, patients received imatinib (600/800mg/day) combined with weekly (20mg) or daily (2.5/5.0mg) everolimus to determine the optimal dose. In phase II, patients were divided into two strata (progression on imatinib only; progression after imatinib and sunitinib/other tyrosine kinase inhibitor) and received everolimus 2.5mg plus imatinib 600mg/day. Primary end point was 4-month progression-free survival (PFS).
Results: Combination treatment was well tolerated. Common adverse events were diarrhea, nausea, fatigue, and anemia. In phase II strata 1 and 2, 4 of 23 (17%) and 13 of 35 (37%) assessable patients, respectively, were progression free at 4 months; median PFS was 1.9 and 3.5 months, and median overall survival was 14.9 and 10.7 months, respectively. In stratum 1, 36% had stable disease (SD) and 54% progressive disease (PD), while in stratum 2, 2% had partial response, 43% SD, and 32% PD.
Conclusion: Predetermined efficacy criteria were met in both strata. The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Benzamides</subject><subject>Biological and medical sciences</subject><subject>Drug Resistance, Neoplasm</subject><subject>Everolimus</subject><subject>everolimus (RAD001)</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>gastrointestinal stromal tumors</subject><subject>Gastrointestinal Stromal Tumors - drug therapy</subject><subject>Gastrointestinal Stromal Tumors - pathology</subject><subject>GIST</subject><subject>Humans</subject><subject>imatinib</subject><subject>Imatinib Mesylate</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Neoplasm Recurrence, Local - drug therapy</subject><subject>Neoplasm Recurrence, Local - pathology</subject><subject>Neoplasm Staging</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - administration & dosage</subject><subject>Pyrimidines - administration & dosage</subject><subject>Salvage Therapy</subject><subject>Sirolimus - administration & dosage</subject><subject>Sirolimus - analogs & derivatives</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>Survival Rate</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><issn>0923-7534</issn><issn>1569-8041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU9vFCEYh4nR2O3q0avhYloPY2FYhpnjptrtmkaN0cR4Ify16AxsgWntrR-gN7-hn0Q2s7bx4IG8vPk9gZcHAJ5h9AqjjhwJ74NXR4O-QKx5AGaYNl3VogV-CGaoq0nFKFnsgf2UviOEmq7uHoO9GlHE2hbPwO0Sbs5FMnD9--bXeg1THvU1DBaaSxND74YxwcOPy9cI4ZfQeajCIJ0X2QUPr1w-h24ojXdyG27K1vic_k2qaJJLWfgMv4mUY3A-m1Qi0cNtO5SaxyHE9AQ8sqJP5umuzsHnkzefjk-rs_er9fHyrFKLBcuV7mqtpdBEEttibbVmkmLTmtqyGluiWquENLSWhDYNVlh2tBCdRMhapTGZg4Pp3E0MF2OZhQ8uKdP3wpswJs4oxYyQsuagmkgVQ0rRWL6J5V3xmmPEt_755J9P_gv_fHfyKAej7-i_wgvwYgeIpERvo_DKpXuOEERQXd9fXMyZn3e5iD94wwij_PTLV45Xb1fvUEv4h8KziTfF26UzkSdV_kIZ7aJRmevg_jPyH6ZHty8</recordid><startdate>20101001</startdate><enddate>20101001</enddate><creator>Schöffski, P.</creator><creator>Reichardt, P.</creator><creator>Blay, J.-Y.</creator><creator>Dumez, H.</creator><creator>Morgan, J.A.</creator><creator>Ray-Coquard, I.</creator><creator>Hollaender, N.</creator><creator>Jappe, A.</creator><creator>Demetri, G.D.</creator><general>Elsevier Ltd</general><general>Oxford University Press</general><scope>6I.</scope><scope>AAFTH</scope><scope>BSCLL</scope><scope>IQODW</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></search><sort><creationdate>20101001</creationdate><title>A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors</title><author>Schöffski, P. ; Reichardt, P. ; Blay, J.-Y. ; Dumez, H. ; Morgan, J.A. ; Ray-Coquard, I. ; Hollaender, N. ; Jappe, A. ; Demetri, G.D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-d92ddbad3b3f81dfdd7b51e8e2f721f3c8fcabe52b35661c1b957b59b00ffcd13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Benzamides</topic><topic>Biological and medical sciences</topic><topic>Drug Resistance, Neoplasm</topic><topic>Everolimus</topic><topic>everolimus (RAD001)</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>gastrointestinal stromal tumors</topic><topic>Gastrointestinal Stromal Tumors - drug therapy</topic><topic>Gastrointestinal Stromal Tumors - pathology</topic><topic>GIST</topic><topic>Humans</topic><topic>imatinib</topic><topic>Imatinib Mesylate</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Neoplasm Recurrence, Local - drug therapy</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Neoplasm Staging</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - administration & dosage</topic><topic>Pyrimidines - administration & dosage</topic><topic>Salvage Therapy</topic><topic>Sirolimus - administration & dosage</topic><topic>Sirolimus - analogs & derivatives</topic><topic>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</topic><topic>Survival Rate</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schöffski, P.</creatorcontrib><creatorcontrib>Reichardt, P.</creatorcontrib><creatorcontrib>Blay, J.-Y.</creatorcontrib><creatorcontrib>Dumez, H.</creatorcontrib><creatorcontrib>Morgan, J.A.</creatorcontrib><creatorcontrib>Ray-Coquard, I.</creatorcontrib><creatorcontrib>Hollaender, N.</creatorcontrib><creatorcontrib>Jappe, A.</creatorcontrib><creatorcontrib>Demetri, G.D.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Istex</collection><collection>Pascal-Francis</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><jtitle>Annals of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schöffski, P.</au><au>Reichardt, P.</au><au>Blay, J.-Y.</au><au>Dumez, H.</au><au>Morgan, J.A.</au><au>Ray-Coquard, I.</au><au>Hollaender, N.</au><au>Jappe, A.</au><au>Demetri, G.D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors</atitle><jtitle>Annals of oncology</jtitle><addtitle>Ann Oncol</addtitle><date>2010-10-01</date><risdate>2010</risdate><volume>21</volume><issue>10</issue><spage>1990</spage><epage>1998</epage><pages>1990-1998</pages><issn>0923-7534</issn><eissn>1569-8041</eissn><abstract>Background: Imatinib is standard therapy for advanced gastrointestinal stromal tumors (GIST), but most patients develop resistance. This phase I–II study assessed the safety and efficacy of coadministering everolimus with imatinib in imatinib-resistant GIST.
Patients and methods: In phase I, patients received imatinib (600/800mg/day) combined with weekly (20mg) or daily (2.5/5.0mg) everolimus to determine the optimal dose. In phase II, patients were divided into two strata (progression on imatinib only; progression after imatinib and sunitinib/other tyrosine kinase inhibitor) and received everolimus 2.5mg plus imatinib 600mg/day. Primary end point was 4-month progression-free survival (PFS).
Results: Combination treatment was well tolerated. Common adverse events were diarrhea, nausea, fatigue, and anemia. In phase II strata 1 and 2, 4 of 23 (17%) and 13 of 35 (37%) assessable patients, respectively, were progression free at 4 months; median PFS was 1.9 and 3.5 months, and median overall survival was 14.9 and 10.7 months, respectively. In stratum 1, 36% had stable disease (SD) and 54% progressive disease (PD), while in stratum 2, 2% had partial response, 43% SD, and 32% PD.
Conclusion: Predetermined efficacy criteria were met in both strata. The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>20507881</pmid><doi>10.1093/annonc/mdq076</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Annals of oncology, 2010-10, Vol.21 (10), p.1990-1998 |
| issn | 0923-7534 1569-8041 |
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| subjects | Adult Aged Aged, 80 and over Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - therapeutic use Benzamides Biological and medical sciences Drug Resistance, Neoplasm Everolimus everolimus (RAD001) Female Gastroenterology. Liver. Pancreas. Abdomen gastrointestinal stromal tumors Gastrointestinal Stromal Tumors - drug therapy Gastrointestinal Stromal Tumors - pathology GIST Humans imatinib Imatinib Mesylate Male Medical sciences Middle Aged Neoplasm Recurrence, Local - drug therapy Neoplasm Recurrence, Local - pathology Neoplasm Staging Pharmacology. Drug treatments Piperazines - administration & dosage Pyrimidines - administration & dosage Salvage Therapy Sirolimus - administration & dosage Sirolimus - analogs & derivatives Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Survival Rate Treatment Outcome Tumors |
| title | A phase I–II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors |
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