A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy
Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after st...
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| Veröffentlicht in: | Journal of neuro-oncology 2016-06, Vol.128 (2), p.259-266 |
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| container_title | Journal of neuro-oncology |
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| creator | Huang, Jiayi Campian, Jian L. Gujar, Amit D. Tran, David D. Lockhart, A. Craig DeWees, Todd A. Tsien, Christina I. Kim, Albert H. |
| description | Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500–1000 mg once daily, in combination with 150–200 mg/m
2
temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2–3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells. |
| doi_str_mv | 10.1007/s11060-016-2104-2 |
| format | Article |
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temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2–3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells.</description><identifier>ISSN: 0167-594X</identifier><identifier>EISSN: 1573-7373</identifier><identifier>DOI: 10.1007/s11060-016-2104-2</identifier><identifier>PMID: 26966095</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Administration, Oral ; Adult ; Aged ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Chemoradiotherapy ; Clinical Study ; Dacarbazine - analogs & derivatives ; Dacarbazine - therapeutic use ; Disulfiram - adverse effects ; Disulfiram - pharmacokinetics ; Disulfiram - therapeutic use ; Dose-Response Relationship, Drug ; Drug Repositioning ; Drug Therapy, Combination ; Female ; Glioblastoma - blood ; Glioblastoma - therapy ; Humans ; Male ; Medicine ; Medicine & Public Health ; Middle Aged ; Neurology ; Oncology ; Proteasome Endopeptidase Complex - blood ; Proteasome Endopeptidase Complex - drug effects ; Proteasome Inhibitors - adverse effects ; Proteasome Inhibitors - pharmacokinetics ; Proteasome Inhibitors - therapeutic use ; Supratentorial Neoplasms - blood ; Supratentorial Neoplasms - therapy ; Treatment Outcome ; Young Adult</subject><ispartof>Journal of neuro-oncology, 2016-06, Vol.128 (2), p.259-266</ispartof><rights>Springer Science+Business Media New York 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-84cc4552c2de01ee83eda8cbb38289e382e3e712fb8b3602e6d5c4640c9f5b773</citedby><cites>FETCH-LOGICAL-c405t-84cc4552c2de01ee83eda8cbb38289e382e3e712fb8b3602e6d5c4640c9f5b773</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/s11060-016-2104-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11060-016-2104-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26966095$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Jiayi</creatorcontrib><creatorcontrib>Campian, Jian L.</creatorcontrib><creatorcontrib>Gujar, Amit D.</creatorcontrib><creatorcontrib>Tran, David D.</creatorcontrib><creatorcontrib>Lockhart, A. Craig</creatorcontrib><creatorcontrib>DeWees, Todd A.</creatorcontrib><creatorcontrib>Tsien, Christina I.</creatorcontrib><creatorcontrib>Kim, Albert H.</creatorcontrib><title>A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy</title><title>Journal of neuro-oncology</title><addtitle>J Neurooncol</addtitle><addtitle>J Neurooncol</addtitle><description>Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500–1000 mg once daily, in combination with 150–200 mg/m
2
temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2–3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells.</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Chemoradiotherapy</subject><subject>Clinical Study</subject><subject>Dacarbazine - analogs & derivatives</subject><subject>Dacarbazine - therapeutic use</subject><subject>Disulfiram - adverse effects</subject><subject>Disulfiram - pharmacokinetics</subject><subject>Disulfiram - therapeutic use</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Repositioning</subject><subject>Drug Therapy, Combination</subject><subject>Female</subject><subject>Glioblastoma - blood</subject><subject>Glioblastoma - therapy</subject><subject>Humans</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Neurology</subject><subject>Oncology</subject><subject>Proteasome Endopeptidase Complex - blood</subject><subject>Proteasome Endopeptidase Complex - drug effects</subject><subject>Proteasome Inhibitors - adverse effects</subject><subject>Proteasome Inhibitors - pharmacokinetics</subject><subject>Proteasome Inhibitors - therapeutic use</subject><subject>Supratentorial Neoplasms - blood</subject><subject>Supratentorial Neoplasms - therapy</subject><subject>Treatment Outcome</subject><subject>Young Adult</subject><issn>0167-594X</issn><issn>1573-7373</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kctq3DAUhkVJaaZJHqCbIMimG7e6WBcvQ-glEOimhe6ELB3PKNiWI8mE6QP0uath0hIK2Uig833_EfwIvaPkAyVEfcyUEkkaQmXDKGkb9gptqFC8UVzxE7SpA9WIrv15it7mfE8IaRWnb9Apk52UpBMb9PsaLzubAd_iXFa_xyXiBMuallgffcjrOIRkJxxm7OLUh9mWEGf8GMoOF5jirzjGKXg4iCWBLXiGx3FfVbuda4bH2zHEfrS5xMliOxRI2O2qmawPsewg2WV_jl4Pdsxw8XSfoR-fP32_-drcfftye3N917iWiNLo1rlWCOaYB0IBNAdvtet7rpnuoJ7AQVE29LrnkjCQXrhWtsR1g-iV4mfo_TF3SfFhhVzMFLKDcbQzxDUbqolW_GBU9Oo_9D6uaa6_M1R1VEjFNa8UPVIuxZwTDGZJYbJpbygxh5LMsSRTuzCHkgyrzuVT8tpP4P8Zf1upADsCuY7mLaRnq19M_QOUrJ8-</recordid><startdate>20160601</startdate><enddate>20160601</enddate><creator>Huang, Jiayi</creator><creator>Campian, Jian L.</creator><creator>Gujar, Amit D.</creator><creator>Tran, David D.</creator><creator>Lockhart, A. Craig</creator><creator>DeWees, Todd A.</creator><creator>Tsien, Christina I.</creator><creator>Kim, Albert H.</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20160601</creationdate><title>A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy</title><author>Huang, Jiayi ; Campian, Jian L. ; Gujar, Amit D. ; Tran, David D. ; Lockhart, A. 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Craig</au><au>DeWees, Todd A.</au><au>Tsien, Christina I.</au><au>Kim, Albert H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy</atitle><jtitle>Journal of neuro-oncology</jtitle><stitle>J Neurooncol</stitle><addtitle>J Neurooncol</addtitle><date>2016-06-01</date><risdate>2016</risdate><volume>128</volume><issue>2</issue><spage>259</spage><epage>266</epage><pages>259-266</pages><issn>0167-594X</issn><eissn>1573-7373</eissn><abstract>Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500–1000 mg once daily, in combination with 150–200 mg/m
2
temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2–3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>26966095</pmid><doi>10.1007/s11060-016-2104-2</doi><tpages>8</tpages></addata></record> |
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| subjects | Administration, Oral Adult Aged Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Chemoradiotherapy Clinical Study Dacarbazine - analogs & derivatives Dacarbazine - therapeutic use Disulfiram - adverse effects Disulfiram - pharmacokinetics Disulfiram - therapeutic use Dose-Response Relationship, Drug Drug Repositioning Drug Therapy, Combination Female Glioblastoma - blood Glioblastoma - therapy Humans Male Medicine Medicine & Public Health Middle Aged Neurology Oncology Proteasome Endopeptidase Complex - blood Proteasome Endopeptidase Complex - drug effects Proteasome Inhibitors - adverse effects Proteasome Inhibitors - pharmacokinetics Proteasome Inhibitors - therapeutic use Supratentorial Neoplasms - blood Supratentorial Neoplasms - therapy Treatment Outcome Young Adult |
| title | A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy |
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