Loading…
The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’
Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS. Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attribute...
Saved in:
| Published in: | European journal of cancer (1990) 2018-05, Vol.94, p.156-167 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c428t-cb8b76a300fe82633251a2d5eca8725c494423a3a9ab19fd91c4c5422993ecc33 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c428t-cb8b76a300fe82633251a2d5eca8725c494423a3a9ab19fd91c4c5422993ecc33 |
| container_end_page | 167 |
| container_issue | |
| container_start_page | 156 |
| container_title | European journal of cancer (1990) |
| container_volume | 94 |
| creator | Schöffski, Patrick Wozniak, Agnieszka Leahy, Michael G. Aamdal, Steinar Rutkowski, Piotr Bauer, Sebastian Richter, Stephan Grünwald, Viktor Debiec-Rychter, Maria Sciot, Raf Geoerger, Birgit Marréaud, Sandrine Collette, Sandra Nzokirantevye, Axelle Strauss, Sandra J. |
| description | Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS.
Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK+ or MET/ALK− subcohorts by assessing the presence or absence of the forkhead box O1 (FOXO1; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety.
Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET+/ALK− patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3–57.8) with a DOR of 52 d. Further MET+/ALK− efficacy end-points were DCR: 14.3% (95% CI: 0.3–57.8), median PFS: 1.3 months (95% CI: 0.5–1.5) and median OS: 5.6 months (95% CI: 0.7–7.0). The remaining MET+/ALK− and MET−/ALK− patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease.
Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment.
EORTC 90101, ClinicalTrials.gov NCT01524926.
•Chemotherapy-refractory ARMS is a clinically aggressive disease.•ARMS is commonly associated with FOXO1 rearrangement, but a low incidence of ALK alterations.•Crizotinib is well-tolerated in chemotherapy-refractory ARMS.•However, crizotinib has limited single-agent activity in chemotherapy-refractory ARMS without ALK rearrangement.•Future trials in this disease should test conventional chemotherapy +/− novel agent. |
| doi_str_mv | 10.1016/j.ejca.2018.02.011 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2018013353</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0959804918301801</els_id><sourcerecordid>2018013353</sourcerecordid><originalsourceid>FETCH-LOGICAL-c428t-cb8b76a300fe82633251a2d5eca8725c494423a3a9ab19fd91c4c5422993ecc33</originalsourceid><addsrcrecordid>eNp9ksGO0zAQQAMCsWXhwpEDGokLlxbbSdoYcVlVXUBaqdKqSNyiiTNpXBK7aztF5bSfAb-3X4JDFw4cOFkav3kz9kySvORsxhmfv93NaKdwJhgvZkzMGOcPkwkvFnLKilw8SiZM5nJasEyeJU-93zHGFkXGniRnQubzxTwVkwcvNi1BODrrtSH4qg16Am1aXelgHSinv9ugja6gtuTB2AAtHghUF4MKu-4IPaHRZtsMHaAK-qDDMRqgJTzoeL13NA2OMFANewyaTPDwTYcWsD6gUTGM3YFshw5ci1Vt-6P16JTt8cRdrr-sIRqcQ7OlPgrewWpwdh8Lw9ptY3kfxdZAE1u-Jh9RFfWmhs1YeMwA28ByrOZg345vFBCcxg4ki38Jd7c_lteri83q7vbns-Rxg52n5_fnefL5crVZfpxerT98Wl5cTVUmijBVVVEt5pgy1lAh5mkqco6izklhsRC5ymSWiRRTlFhx2dSSq0zlmRBSpqRUmp4nb07evbM3A_lQ9tor6jo0ZAdfjnNlPE3zEX39D7qzgzOxu0gt0pxJPueREidKxXF6R025d7pHdyw5K8eNKXfluDG_zSUTZdyYmPTqXj1UPdV_U_6sSATenwCKf3HQ5Eqv4hDj3LQjFcra6v_5fwHXT9gk</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2073509161</pqid></control><display><type>article</type><title>The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’</title><source>ScienceDirect Freedom Collection</source><creator>Schöffski, Patrick ; Wozniak, Agnieszka ; Leahy, Michael G. ; Aamdal, Steinar ; Rutkowski, Piotr ; Bauer, Sebastian ; Richter, Stephan ; Grünwald, Viktor ; Debiec-Rychter, Maria ; Sciot, Raf ; Geoerger, Birgit ; Marréaud, Sandrine ; Collette, Sandra ; Nzokirantevye, Axelle ; Strauss, Sandra J.</creator><creatorcontrib>Schöffski, Patrick ; Wozniak, Agnieszka ; Leahy, Michael G. ; Aamdal, Steinar ; Rutkowski, Piotr ; Bauer, Sebastian ; Richter, Stephan ; Grünwald, Viktor ; Debiec-Rychter, Maria ; Sciot, Raf ; Geoerger, Birgit ; Marréaud, Sandrine ; Collette, Sandra ; Nzokirantevye, Axelle ; Strauss, Sandra J.</creatorcontrib><description>Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS.
Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK+ or MET/ALK− subcohorts by assessing the presence or absence of the forkhead box O1 (FOXO1; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety.
Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET+/ALK− patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3–57.8) with a DOR of 52 d. Further MET+/ALK− efficacy end-points were DCR: 14.3% (95% CI: 0.3–57.8), median PFS: 1.3 months (95% CI: 0.5–1.5) and median OS: 5.6 months (95% CI: 0.7–7.0). The remaining MET+/ALK− and MET−/ALK− patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease.
Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment.
EORTC 90101, ClinicalTrials.gov NCT01524926.
•Chemotherapy-refractory ARMS is a clinically aggressive disease.•ARMS is commonly associated with FOXO1 rearrangement, but a low incidence of ALK alterations.•Crizotinib is well-tolerated in chemotherapy-refractory ARMS.•However, crizotinib has limited single-agent activity in chemotherapy-refractory ARMS without ALK rearrangement.•Future trials in this disease should test conventional chemotherapy +/− novel agent.</description><identifier>ISSN: 0959-8049</identifier><identifier>EISSN: 1879-0852</identifier><identifier>DOI: 10.1016/j.ejca.2018.02.011</identifier><identifier>PMID: 29567632</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; ALK ; ALK protein ; Alveolar rhabdomyosarcoma ; Alveoli ; Anorexia ; Antineoplastic Agents - therapeutic use ; ARMS ; c-Met protein ; Cancer ; Cancer therapies ; Chemotherapy ; Child ; Clinical trials ; Confidence intervals ; Constipation ; Crizotinib ; Crizotinib - therapeutic use ; Disease control ; Enzyme inhibitors ; Fatalities ; Fatigue ; Female ; Forkhead Box Protein O1 - genetics ; Forkhead protein ; FOXO1 ; FOXO1 protein ; Gene expression ; Gene Rearrangement ; Humans ; Inhibitor drugs ; Kinases ; Lymphoma ; Male ; Metastases ; Metastasis ; Middle Aged ; Molecular chains ; Nausea ; Patients ; Progression-Free Survival ; Protein Kinase Inhibitors - therapeutic use ; Rhabdomyosarcoma ; Rhabdomyosarcoma, Alveolar - drug therapy ; Rhabdomyosarcoma, Alveolar - genetics ; Survival ; Targeted cancer therapy ; Tumors ; Tyrosine ; Tyrosine kinase inhibitors ; Vomiting ; Young Adult</subject><ispartof>European journal of cancer (1990), 2018-05, Vol.94, p.156-167</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Science Ltd. May 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-cb8b76a300fe82633251a2d5eca8725c494423a3a9ab19fd91c4c5422993ecc33</citedby><cites>FETCH-LOGICAL-c428t-cb8b76a300fe82633251a2d5eca8725c494423a3a9ab19fd91c4c5422993ecc33</cites><orcidid>0000-0003-2083-7687 ; 0000-0001-5949-8120 ; 0000-0001-5980-030X ; 0000-0002-8920-5429</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29567632$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schöffski, Patrick</creatorcontrib><creatorcontrib>Wozniak, Agnieszka</creatorcontrib><creatorcontrib>Leahy, Michael G.</creatorcontrib><creatorcontrib>Aamdal, Steinar</creatorcontrib><creatorcontrib>Rutkowski, Piotr</creatorcontrib><creatorcontrib>Bauer, Sebastian</creatorcontrib><creatorcontrib>Richter, Stephan</creatorcontrib><creatorcontrib>Grünwald, Viktor</creatorcontrib><creatorcontrib>Debiec-Rychter, Maria</creatorcontrib><creatorcontrib>Sciot, Raf</creatorcontrib><creatorcontrib>Geoerger, Birgit</creatorcontrib><creatorcontrib>Marréaud, Sandrine</creatorcontrib><creatorcontrib>Collette, Sandra</creatorcontrib><creatorcontrib>Nzokirantevye, Axelle</creatorcontrib><creatorcontrib>Strauss, Sandra J.</creatorcontrib><title>The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’</title><title>European journal of cancer (1990)</title><addtitle>Eur J Cancer</addtitle><description>Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS.
Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK+ or MET/ALK− subcohorts by assessing the presence or absence of the forkhead box O1 (FOXO1; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety.
Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET+/ALK− patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3–57.8) with a DOR of 52 d. Further MET+/ALK− efficacy end-points were DCR: 14.3% (95% CI: 0.3–57.8), median PFS: 1.3 months (95% CI: 0.5–1.5) and median OS: 5.6 months (95% CI: 0.7–7.0). The remaining MET+/ALK− and MET−/ALK− patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease.
Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment.
EORTC 90101, ClinicalTrials.gov NCT01524926.
•Chemotherapy-refractory ARMS is a clinically aggressive disease.•ARMS is commonly associated with FOXO1 rearrangement, but a low incidence of ALK alterations.•Crizotinib is well-tolerated in chemotherapy-refractory ARMS.•However, crizotinib has limited single-agent activity in chemotherapy-refractory ARMS without ALK rearrangement.•Future trials in this disease should test conventional chemotherapy +/− novel agent.</description><subject>Adolescent</subject><subject>Adult</subject><subject>ALK</subject><subject>ALK protein</subject><subject>Alveolar rhabdomyosarcoma</subject><subject>Alveoli</subject><subject>Anorexia</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>ARMS</subject><subject>c-Met protein</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Chemotherapy</subject><subject>Child</subject><subject>Clinical trials</subject><subject>Confidence intervals</subject><subject>Constipation</subject><subject>Crizotinib</subject><subject>Crizotinib - therapeutic use</subject><subject>Disease control</subject><subject>Enzyme inhibitors</subject><subject>Fatalities</subject><subject>Fatigue</subject><subject>Female</subject><subject>Forkhead Box Protein O1 - genetics</subject><subject>Forkhead protein</subject><subject>FOXO1</subject><subject>FOXO1 protein</subject><subject>Gene expression</subject><subject>Gene Rearrangement</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Kinases</subject><subject>Lymphoma</subject><subject>Male</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Molecular chains</subject><subject>Nausea</subject><subject>Patients</subject><subject>Progression-Free Survival</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Rhabdomyosarcoma</subject><subject>Rhabdomyosarcoma, Alveolar - drug therapy</subject><subject>Rhabdomyosarcoma, Alveolar - genetics</subject><subject>Survival</subject><subject>Targeted cancer therapy</subject><subject>Tumors</subject><subject>Tyrosine</subject><subject>Tyrosine kinase inhibitors</subject><subject>Vomiting</subject><subject>Young Adult</subject><issn>0959-8049</issn><issn>1879-0852</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp9ksGO0zAQQAMCsWXhwpEDGokLlxbbSdoYcVlVXUBaqdKqSNyiiTNpXBK7aztF5bSfAb-3X4JDFw4cOFkav3kz9kySvORsxhmfv93NaKdwJhgvZkzMGOcPkwkvFnLKilw8SiZM5nJasEyeJU-93zHGFkXGniRnQubzxTwVkwcvNi1BODrrtSH4qg16Am1aXelgHSinv9ugja6gtuTB2AAtHghUF4MKu-4IPaHRZtsMHaAK-qDDMRqgJTzoeL13NA2OMFANewyaTPDwTYcWsD6gUTGM3YFshw5ci1Vt-6P16JTt8cRdrr-sIRqcQ7OlPgrewWpwdh8Lw9ptY3kfxdZAE1u-Jh9RFfWmhs1YeMwA28ByrOZg345vFBCcxg4ki38Jd7c_lteri83q7vbns-Rxg52n5_fnefL5crVZfpxerT98Wl5cTVUmijBVVVEt5pgy1lAh5mkqco6izklhsRC5ymSWiRRTlFhx2dSSq0zlmRBSpqRUmp4nb07evbM3A_lQ9tor6jo0ZAdfjnNlPE3zEX39D7qzgzOxu0gt0pxJPueREidKxXF6R025d7pHdyw5K8eNKXfluDG_zSUTZdyYmPTqXj1UPdV_U_6sSATenwCKf3HQ5Eqv4hDj3LQjFcra6v_5fwHXT9gk</recordid><startdate>201805</startdate><enddate>201805</enddate><creator>Schöffski, Patrick</creator><creator>Wozniak, Agnieszka</creator><creator>Leahy, Michael G.</creator><creator>Aamdal, Steinar</creator><creator>Rutkowski, Piotr</creator><creator>Bauer, Sebastian</creator><creator>Richter, Stephan</creator><creator>Grünwald, Viktor</creator><creator>Debiec-Rychter, Maria</creator><creator>Sciot, Raf</creator><creator>Geoerger, Birgit</creator><creator>Marréaud, Sandrine</creator><creator>Collette, Sandra</creator><creator>Nzokirantevye, Axelle</creator><creator>Strauss, Sandra J.</creator><general>Elsevier Ltd</general><general>Elsevier Science Ltd</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>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2083-7687</orcidid><orcidid>https://orcid.org/0000-0001-5949-8120</orcidid><orcidid>https://orcid.org/0000-0001-5980-030X</orcidid><orcidid>https://orcid.org/0000-0002-8920-5429</orcidid></search><sort><creationdate>201805</creationdate><title>The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’</title><author>Schöffski, Patrick ; Wozniak, Agnieszka ; Leahy, Michael G. ; Aamdal, Steinar ; Rutkowski, Piotr ; Bauer, Sebastian ; Richter, Stephan ; Grünwald, Viktor ; Debiec-Rychter, Maria ; Sciot, Raf ; Geoerger, Birgit ; Marréaud, Sandrine ; Collette, Sandra ; Nzokirantevye, Axelle ; Strauss, Sandra J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-cb8b76a300fe82633251a2d5eca8725c494423a3a9ab19fd91c4c5422993ecc33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>ALK</topic><topic>ALK protein</topic><topic>Alveolar rhabdomyosarcoma</topic><topic>Alveoli</topic><topic>Anorexia</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>ARMS</topic><topic>c-Met protein</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Chemotherapy</topic><topic>Child</topic><topic>Clinical trials</topic><topic>Confidence intervals</topic><topic>Constipation</topic><topic>Crizotinib</topic><topic>Crizotinib - therapeutic use</topic><topic>Disease control</topic><topic>Enzyme inhibitors</topic><topic>Fatalities</topic><topic>Fatigue</topic><topic>Female</topic><topic>Forkhead Box Protein O1 - genetics</topic><topic>Forkhead protein</topic><topic>FOXO1</topic><topic>FOXO1 protein</topic><topic>Gene expression</topic><topic>Gene Rearrangement</topic><topic>Humans</topic><topic>Inhibitor drugs</topic><topic>Kinases</topic><topic>Lymphoma</topic><topic>Male</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Molecular chains</topic><topic>Nausea</topic><topic>Patients</topic><topic>Progression-Free Survival</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Rhabdomyosarcoma</topic><topic>Rhabdomyosarcoma, Alveolar - drug therapy</topic><topic>Rhabdomyosarcoma, Alveolar - genetics</topic><topic>Survival</topic><topic>Targeted cancer therapy</topic><topic>Tumors</topic><topic>Tyrosine</topic><topic>Tyrosine kinase inhibitors</topic><topic>Vomiting</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schöffski, Patrick</creatorcontrib><creatorcontrib>Wozniak, Agnieszka</creatorcontrib><creatorcontrib>Leahy, Michael G.</creatorcontrib><creatorcontrib>Aamdal, Steinar</creatorcontrib><creatorcontrib>Rutkowski, Piotr</creatorcontrib><creatorcontrib>Bauer, Sebastian</creatorcontrib><creatorcontrib>Richter, Stephan</creatorcontrib><creatorcontrib>Grünwald, Viktor</creatorcontrib><creatorcontrib>Debiec-Rychter, Maria</creatorcontrib><creatorcontrib>Sciot, Raf</creatorcontrib><creatorcontrib>Geoerger, Birgit</creatorcontrib><creatorcontrib>Marréaud, Sandrine</creatorcontrib><creatorcontrib>Collette, Sandra</creatorcontrib><creatorcontrib>Nzokirantevye, Axelle</creatorcontrib><creatorcontrib>Strauss, Sandra J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</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><jtitle>European journal of cancer (1990)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schöffski, Patrick</au><au>Wozniak, Agnieszka</au><au>Leahy, Michael G.</au><au>Aamdal, Steinar</au><au>Rutkowski, Piotr</au><au>Bauer, Sebastian</au><au>Richter, Stephan</au><au>Grünwald, Viktor</au><au>Debiec-Rychter, Maria</au><au>Sciot, Raf</au><au>Geoerger, Birgit</au><au>Marréaud, Sandrine</au><au>Collette, Sandra</au><au>Nzokirantevye, Axelle</au><au>Strauss, Sandra J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’</atitle><jtitle>European journal of cancer (1990)</jtitle><addtitle>Eur J Cancer</addtitle><date>2018-05</date><risdate>2018</risdate><volume>94</volume><spage>156</spage><epage>167</epage><pages>156-167</pages><issn>0959-8049</issn><eissn>1879-0852</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><abstract>Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS.
Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK+ or MET/ALK− subcohorts by assessing the presence or absence of the forkhead box O1 (FOXO1; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety.
Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET+/ALK− patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3–57.8) with a DOR of 52 d. Further MET+/ALK− efficacy end-points were DCR: 14.3% (95% CI: 0.3–57.8), median PFS: 1.3 months (95% CI: 0.5–1.5) and median OS: 5.6 months (95% CI: 0.7–7.0). The remaining MET+/ALK− and MET−/ALK− patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease.
Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment.
EORTC 90101, ClinicalTrials.gov NCT01524926.
•Chemotherapy-refractory ARMS is a clinically aggressive disease.•ARMS is commonly associated with FOXO1 rearrangement, but a low incidence of ALK alterations.•Crizotinib is well-tolerated in chemotherapy-refractory ARMS.•However, crizotinib has limited single-agent activity in chemotherapy-refractory ARMS without ALK rearrangement.•Future trials in this disease should test conventional chemotherapy +/− novel agent.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29567632</pmid><doi>10.1016/j.ejca.2018.02.011</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-2083-7687</orcidid><orcidid>https://orcid.org/0000-0001-5949-8120</orcidid><orcidid>https://orcid.org/0000-0001-5980-030X</orcidid><orcidid>https://orcid.org/0000-0002-8920-5429</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0959-8049 |
| ispartof | European journal of cancer (1990), 2018-05, Vol.94, p.156-167 |
| issn | 0959-8049 1879-0852 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2018013353 |
| source | ScienceDirect Freedom Collection |
| subjects | Adolescent Adult ALK ALK protein Alveolar rhabdomyosarcoma Alveoli Anorexia Antineoplastic Agents - therapeutic use ARMS c-Met protein Cancer Cancer therapies Chemotherapy Child Clinical trials Confidence intervals Constipation Crizotinib Crizotinib - therapeutic use Disease control Enzyme inhibitors Fatalities Fatigue Female Forkhead Box Protein O1 - genetics Forkhead protein FOXO1 FOXO1 protein Gene expression Gene Rearrangement Humans Inhibitor drugs Kinases Lymphoma Male Metastases Metastasis Middle Aged Molecular chains Nausea Patients Progression-Free Survival Protein Kinase Inhibitors - therapeutic use Rhabdomyosarcoma Rhabdomyosarcoma, Alveolar - drug therapy Rhabdomyosarcoma, Alveolar - genetics Survival Targeted cancer therapy Tumors Tyrosine Tyrosine kinase inhibitors Vomiting Young Adult |
| title | The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’ |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T04%3A48%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20tyrosine%20kinase%20inhibitor%20crizotinib%20does%20not%20have%20clinically%20meaningful%20activity%20in%20heavily%20pre-treated%20patients%20with%20advanced%20alveolar%20rhabdomyosarcoma%20with%20FOXO%20rearrangement:%20European%20Organisation%20for%20Research%20and%20Treatment%20of%20Cancer%20phase%202%20trial%2090101%20%E2%80%98CREATE%E2%80%99&rft.jtitle=European%20journal%20of%20cancer%20(1990)&rft.au=Sch%C3%B6ffski,%20Patrick&rft.date=2018-05&rft.volume=94&rft.spage=156&rft.epage=167&rft.pages=156-167&rft.issn=0959-8049&rft.eissn=1879-0852&rft_id=info:doi/10.1016/j.ejca.2018.02.011&rft_dat=%3Cproquest_cross%3E2018013353%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c428t-cb8b76a300fe82633251a2d5eca8725c494423a3a9ab19fd91c4c5422993ecc33%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2073509161&rft_id=info:pmid/29567632&rfr_iscdi=true |