A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors
Summary Background Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first cli...
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| Veröffentlicht in: | Investigational new drugs 2015-10, Vol.33 (5), p.1058-1067 |
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| creator | Kasuga, Akiyoshi Nakagawa, Kazuhiko Nagashima, Fumio Shimizu, Toshio Naruge, Daisuke Nishina, Shinichi Kitamura, Hiroshi Kurata, Takayasu Takasu, Atsuko Fujisaka, Yasuhito Okamoto, Wataru Nishimura, Yuichiro Mukaiyama, Akihira Matsushita, Hideki Furuse, Junji |
| description | Summary
Background
Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results.
Methods
In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m
2
).
Results
In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2).
Conclusions
Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.) |
| doi_str_mv | 10.1007/s10637-015-0270-2 |
| format | Article |
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Background
Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results.
Methods
In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m
2
).
Results
In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2).
Conclusions
Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-015-0270-2</identifier><identifier>PMID: 26259955</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject><![CDATA[Adenosine triphosphate ; Adult ; Aged ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Area Under Curve ; Asian Continental Ancestry Group ; Cancer ; Cancer therapies ; Clinical trials ; Deoxycytidine - administration & dosage ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - therapeutic use ; Dose-Response Relationship, Drug ; Drug dosages ; Drug Therapy, Combination ; FDA approval ; Female ; Gemcitabine ; Hospitals ; Humans ; Inhibitor drugs ; Japan ; Kinases ; Lung diseases ; Male ; Maximum Tolerated Dose ; Medicine ; Medicine & Public Health ; Middle Aged ; Mutation ; Neoplasms - drug therapy ; Oncology ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Patients ; Pharmacokinetics ; Pharmacology/Toxicology ; Phase I Studies ; Pyridones - administration & dosage ; Pyridones - adverse effects ; Pyridones - pharmacokinetics ; Pyridones - therapeutic use ; Pyrimidinones - administration & dosage ; Pyrimidinones - adverse effects ; Pyrimidinones - pharmacokinetics ; Pyrimidinones - therapeutic use ; Side effects ; Solid tumors ; Studies ; Toxicity ; Tumors]]></subject><ispartof>Investigational new drugs, 2015-10, Vol.33 (5), p.1058-1067</ispartof><rights>Springer Science+Business Media New York 2015</rights><rights>Springer Science+Business Media New York 2015.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-3e33a69e0073c75f78adc57b0c66c333a68359f3c29e405fb8f16d2cc5e06de73</citedby><cites>FETCH-LOGICAL-c470t-3e33a69e0073c75f78adc57b0c66c333a68359f3c29e405fb8f16d2cc5e06de73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10637-015-0270-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-015-0270-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26259955$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kasuga, Akiyoshi</creatorcontrib><creatorcontrib>Nakagawa, Kazuhiko</creatorcontrib><creatorcontrib>Nagashima, Fumio</creatorcontrib><creatorcontrib>Shimizu, Toshio</creatorcontrib><creatorcontrib>Naruge, Daisuke</creatorcontrib><creatorcontrib>Nishina, Shinichi</creatorcontrib><creatorcontrib>Kitamura, Hiroshi</creatorcontrib><creatorcontrib>Kurata, Takayasu</creatorcontrib><creatorcontrib>Takasu, Atsuko</creatorcontrib><creatorcontrib>Fujisaka, Yasuhito</creatorcontrib><creatorcontrib>Okamoto, Wataru</creatorcontrib><creatorcontrib>Nishimura, Yuichiro</creatorcontrib><creatorcontrib>Mukaiyama, Akihira</creatorcontrib><creatorcontrib>Matsushita, Hideki</creatorcontrib><creatorcontrib>Furuse, Junji</creatorcontrib><title>A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
Background
Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results.
Methods
In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m
2
).
Results
In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2).
Conclusions
Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)</description><subject>Adenosine triphosphate</subject><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Area Under Curve</subject><subject>Asian Continental Ancestry Group</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Clinical trials</subject><subject>Deoxycytidine - administration & dosage</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - therapeutic use</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug dosages</subject><subject>Drug Therapy, Combination</subject><subject>FDA approval</subject><subject>Female</subject><subject>Gemcitabine</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Japan</subject><subject>Kinases</subject><subject>Lung diseases</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Neoplasms - drug therapy</subject><subject>Oncology</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Patients</subject><subject>Pharmacokinetics</subject><subject>Pharmacology/Toxicology</subject><subject>Phase I Studies</subject><subject>Pyridones - administration & dosage</subject><subject>Pyridones - adverse effects</subject><subject>Pyridones - pharmacokinetics</subject><subject>Pyridones - therapeutic use</subject><subject>Pyrimidinones - administration & dosage</subject><subject>Pyrimidinones - adverse effects</subject><subject>Pyrimidinones - pharmacokinetics</subject><subject>Pyrimidinones - therapeutic use</subject><subject>Side effects</subject><subject>Solid tumors</subject><subject>Studies</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp9kcFuFSEUhomxsdfqA7gxJG50Me0BBrgsm0brtU1cqGvCANPS3IERGE2fwNeWm6nGjV2R8H_nPzn5EHpF4JQAyLNCQDDZAeEdUAkdfYI2hEvWgejFU7QBImQnlJLH6HkpdwDAlOyfoWMqKFeK8w36dY7nW1M83p3tBlzq4u5xGnHNZvI1xDDgt5dfrgihQAl9h80-RY9NdDhEbNM0hGhqSBH_DPUW3_jJhmrapz_kn8xsom_dc2N8rGWljPthovUOl7QPDtdlSrm8QEej2Rf_8uE9Qd8-vP968bG7_ny5uzi_7mwvoXbMM2aE8u16ZiUf5dY4y-UAVgjLDtmWcTUyS5XvgY_DdiTCUWu5B-G8ZCfozdo75_R98aXqu7Tk2FZqKhSXhFO5fYwiktCeK1DQKLJSNqdSsh_1nMNk8r0moA-C9CpIN0H6IEjTNvP6oXkZJu_-Tvwx0gC6AqVF8cbnf1b_t_U3P_SZeQ</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Kasuga, Akiyoshi</creator><creator>Nakagawa, Kazuhiko</creator><creator>Nagashima, Fumio</creator><creator>Shimizu, Toshio</creator><creator>Naruge, Daisuke</creator><creator>Nishina, Shinichi</creator><creator>Kitamura, Hiroshi</creator><creator>Kurata, Takayasu</creator><creator>Takasu, Atsuko</creator><creator>Fujisaka, Yasuhito</creator><creator>Okamoto, Wataru</creator><creator>Nishimura, Yuichiro</creator><creator>Mukaiyama, Akihira</creator><creator>Matsushita, Hideki</creator><creator>Furuse, Junji</creator><general>Springer US</general><general>Springer Nature 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phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors</title><author>Kasuga, Akiyoshi ; Nakagawa, Kazuhiko ; Nagashima, Fumio ; Shimizu, Toshio ; Naruge, Daisuke ; Nishina, Shinichi ; Kitamura, Hiroshi ; Kurata, Takayasu ; Takasu, Atsuko ; Fujisaka, Yasuhito ; Okamoto, Wataru ; Nishimura, Yuichiro ; Mukaiyama, Akihira ; Matsushita, Hideki ; Furuse, Junji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-3e33a69e0073c75f78adc57b0c66c333a68359f3c29e405fb8f16d2cc5e06de73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adenosine triphosphate</topic><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Area Under Curve</topic><topic>Asian Continental Ancestry Group</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Clinical trials</topic><topic>Deoxycytidine - administration & dosage</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxycytidine - therapeutic use</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug dosages</topic><topic>Drug Therapy, Combination</topic><topic>FDA approval</topic><topic>Female</topic><topic>Gemcitabine</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Inhibitor drugs</topic><topic>Japan</topic><topic>Kinases</topic><topic>Lung diseases</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Neoplasms - drug therapy</topic><topic>Oncology</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Patients</topic><topic>Pharmacokinetics</topic><topic>Pharmacology/Toxicology</topic><topic>Phase I Studies</topic><topic>Pyridones - administration & dosage</topic><topic>Pyridones - adverse effects</topic><topic>Pyridones - pharmacokinetics</topic><topic>Pyridones - therapeutic use</topic><topic>Pyrimidinones - administration & dosage</topic><topic>Pyrimidinones - adverse effects</topic><topic>Pyrimidinones - pharmacokinetics</topic><topic>Pyrimidinones - therapeutic use</topic><topic>Side effects</topic><topic>Solid tumors</topic><topic>Studies</topic><topic>Toxicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kasuga, Akiyoshi</creatorcontrib><creatorcontrib>Nakagawa, Kazuhiko</creatorcontrib><creatorcontrib>Nagashima, Fumio</creatorcontrib><creatorcontrib>Shimizu, Toshio</creatorcontrib><creatorcontrib>Naruge, Daisuke</creatorcontrib><creatorcontrib>Nishina, Shinichi</creatorcontrib><creatorcontrib>Kitamura, Hiroshi</creatorcontrib><creatorcontrib>Kurata, Takayasu</creatorcontrib><creatorcontrib>Takasu, Atsuko</creatorcontrib><creatorcontrib>Fujisaka, Yasuhito</creatorcontrib><creatorcontrib>Okamoto, Wataru</creatorcontrib><creatorcontrib>Nishimura, Yuichiro</creatorcontrib><creatorcontrib>Mukaiyama, Akihira</creatorcontrib><creatorcontrib>Matsushita, Hideki</creatorcontrib><creatorcontrib>Furuse, Junji</creatorcontrib><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>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Access via ABI/INFORM (ProQuest)</collection><collection>ABI/INFORM Global (PDF only)</collection><collection>Health & 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gemcitabine in Japanese patients with advanced solid tumors</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>33</volume><issue>5</issue><spage>1058</spage><epage>1067</epage><pages>1058-1067</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>Summary
Background
Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results.
Methods
In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m
2
).
Results
In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2).
Conclusions
Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)</abstract><cop>New York</cop><pub>Springer US</pub><pmid>26259955</pmid><doi>10.1007/s10637-015-0270-2</doi><tpages>10</tpages></addata></record> |
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| identifier | ISSN: 0167-6997 |
| ispartof | Investigational new drugs, 2015-10, Vol.33 (5), p.1058-1067 |
| issn | 0167-6997 1573-0646 |
| language | eng |
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| source | MEDLINE; SpringerNature Journals |
| subjects | Adenosine triphosphate Adult Aged Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Area Under Curve Asian Continental Ancestry Group Cancer Cancer therapies Clinical trials Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Deoxycytidine - therapeutic use Dose-Response Relationship, Drug Drug dosages Drug Therapy, Combination FDA approval Female Gemcitabine Hospitals Humans Inhibitor drugs Japan Kinases Lung diseases Male Maximum Tolerated Dose Medicine Medicine & Public Health Middle Aged Mutation Neoplasms - drug therapy Oncology Pancreatic cancer Pancreatic Neoplasms - drug therapy Patients Pharmacokinetics Pharmacology/Toxicology Phase I Studies Pyridones - administration & dosage Pyridones - adverse effects Pyridones - pharmacokinetics Pyridones - therapeutic use Pyrimidinones - administration & dosage Pyrimidinones - adverse effects Pyrimidinones - pharmacokinetics Pyrimidinones - therapeutic use Side effects Solid tumors Studies Toxicity Tumors |
| title | A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-29T14%3A29%3A03IST&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=A%20phase%20I/Ib%20study%20of%20trametinib%20(GSK1120212)%20alone%20and%20in%20combination%20with%20gemcitabine%20in%20Japanese%20patients%20with%20advanced%20solid%20tumors&rft.jtitle=Investigational%20new%20drugs&rft.au=Kasuga,%20Akiyoshi&rft.date=2015-10-01&rft.volume=33&rft.issue=5&rft.spage=1058&rft.epage=1067&rft.pages=1058-1067&rft.issn=0167-6997&rft.eissn=1573-0646&rft_id=info:doi/10.1007/s10637-015-0270-2&rft_dat=%3Cproquest_cross%3E3807768851%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1712459090&rft_id=info:pmid/26259955&rfr_iscdi=true |