Phase I Clinical Trial of BMS-247550, A Derivative of Epothilone B, Using Accelerated Titration 2B Design
Purpose: BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated titration “2B” design, of BMS...
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| Veröffentlicht in: | Clinical cancer research 2005-09, Vol.11 (17), p.6233-6239 |
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| creator | GADGEEL, Shirish M WOZNIAK, Antoinette BOINPALLY, Ramesh R WIEGAND, Richard HEILBRUN, Lance K JAIN, Vikas PARCHMENT, Ralph COLEVAS, Dimitrios COHEN, Marvin B LORUSSO, Patricia M |
| description | Purpose: BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive
antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated
titration “2B” design, of BMS-247550 given as a 1-hour infusion every 3 weeks.
Experimental Design: Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles
(1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m 2 . All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists.
Results: First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m 2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m 2 . Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m 2 . Grade 1 to 2 peripheral neuropathy was also observed. Other grade 1 to 2 toxicities were myalgias, arthralgias, rash, hand/foot
syndrome, and mucositis. AUC and C max seemed proportional to the dose and the DLT. Development of neutropenia with BMS-247550 is related to the duration of drug
exposure above a threshold.
Conclusions: The maximum tolerated dose (MTD) of BMS-247550 is 40 mg/m 2 given every 3 weeks. Neutropenia is the DLT. The accelerated titration “2B” design may help in determining MTD with fewer
patients enrolled and more being treated closer to the MTD. However, the accelerated titration design did not seem to shorten
the study duration. |
| doi_str_mv | 10.1158/1078-0432.CCR-05-0127 |
| format | Article |
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antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated
titration “2B” design, of BMS-247550 given as a 1-hour infusion every 3 weeks.
Experimental Design: Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles
(1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m 2 . All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists.
Results: First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m 2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m 2 . Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m 2 . Grade 1 to 2 peripheral neuropathy was also observed. Other grade 1 to 2 toxicities were myalgias, arthralgias, rash, hand/foot
syndrome, and mucositis. AUC and C max seemed proportional to the dose and the DLT. Development of neutropenia with BMS-247550 is related to the duration of drug
exposure above a threshold.
Conclusions: The maximum tolerated dose (MTD) of BMS-247550 is 40 mg/m 2 given every 3 weeks. Neutropenia is the DLT. The accelerated titration “2B” design may help in determining MTD with fewer
patients enrolled and more being treated closer to the MTD. However, the accelerated titration design did not seem to shorten
the study duration.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-05-0127</identifier><identifier>PMID: 16144926</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Biological and medical sciences ; Epothilone ; Epothilones - administration & dosage ; Epothilones - pharmacokinetics ; Female ; Humans ; Infusions, Intravenous ; Male ; Maximum Tolerated Dose ; Medical sciences ; Middle Aged ; MTD ; Neoplasms - drug therapy ; neutropenia ; pharmacokinetics ; Pharmacology. Drug treatments ; Phase I</subject><ispartof>Clinical cancer research, 2005-09, Vol.11 (17), p.6233-6239</ispartof><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c317t-2c74493fe8efcce771d9714324e1179b527a736774a306044f388607dc80e6813</citedby><cites>FETCH-LOGICAL-c317t-2c74493fe8efcce771d9714324e1179b527a736774a306044f388607dc80e6813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,3357,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17102651$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16144926$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GADGEEL, Shirish M</creatorcontrib><creatorcontrib>WOZNIAK, Antoinette</creatorcontrib><creatorcontrib>BOINPALLY, Ramesh R</creatorcontrib><creatorcontrib>WIEGAND, Richard</creatorcontrib><creatorcontrib>HEILBRUN, Lance K</creatorcontrib><creatorcontrib>JAIN, Vikas</creatorcontrib><creatorcontrib>PARCHMENT, Ralph</creatorcontrib><creatorcontrib>COLEVAS, Dimitrios</creatorcontrib><creatorcontrib>COHEN, Marvin B</creatorcontrib><creatorcontrib>LORUSSO, Patricia M</creatorcontrib><title>Phase I Clinical Trial of BMS-247550, A Derivative of Epothilone B, Using Accelerated Titration 2B Design</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive
antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated
titration “2B” design, of BMS-247550 given as a 1-hour infusion every 3 weeks.
Experimental Design: Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles
(1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m 2 . All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists.
Results: First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m 2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m 2 . Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m 2 . Grade 1 to 2 peripheral neuropathy was also observed. Other grade 1 to 2 toxicities were myalgias, arthralgias, rash, hand/foot
syndrome, and mucositis. AUC and C max seemed proportional to the dose and the DLT. Development of neutropenia with BMS-247550 is related to the duration of drug
exposure above a threshold.
Conclusions: The maximum tolerated dose (MTD) of BMS-247550 is 40 mg/m 2 given every 3 weeks. Neutropenia is the DLT. The accelerated titration “2B” design may help in determining MTD with fewer
patients enrolled and more being treated closer to the MTD. However, the accelerated titration design did not seem to shorten
the study duration.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Epothilone</subject><subject>Epothilones - administration & dosage</subject><subject>Epothilones - pharmacokinetics</subject><subject>Female</subject><subject>Humans</subject><subject>Infusions, Intravenous</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>MTD</subject><subject>Neoplasms - drug therapy</subject><subject>neutropenia</subject><subject>pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Phase I</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkV1P2zAUhq1paDC2nzDkmyEhkeLjz_SyDWxDKmLayrVl3JPGKE2KnYL493PUTtzYR_Jzjl8_JuQbsAmAKq-AmbJgUvBJVf0pmCoYcPOBnIBSphBcq4-5_s8ck88pPTEGEpj8RI5Bg5RTrk9I-N24hPSWVm3ognctXcaQ176m87u_BZdGKXZJZ_QaY3hxQ3jB8exm2w9NaPsO6fySPqTQrenMe2wxugFXdBmGXIS-o3yeW1NYd1_IUe3ahF8P-yl5-HGzrH4Vi_uft9VsUXgBZii4NzmaqLHEOg80BlZTA_kNEgHM9FFx44zQxkgnmGZS1qIsNTMrXzLUJYhTcr6fu4398w7TYDch5WSt67DfJctBgNJyBNUe9LFPKWJttzFsXHyzwOzo2I7-7OjPZseWKTs6zn1nhwt2jxtcvXcdpGbg-wFwKRuto-t8SO-cAZb_ZwxwseeasG5eQ0TrM4kxYkIXfZNDZNhqLoT4B0jTjjM</recordid><startdate>20050901</startdate><enddate>20050901</enddate><creator>GADGEEL, Shirish M</creator><creator>WOZNIAK, Antoinette</creator><creator>BOINPALLY, Ramesh R</creator><creator>WIEGAND, Richard</creator><creator>HEILBRUN, Lance K</creator><creator>JAIN, Vikas</creator><creator>PARCHMENT, Ralph</creator><creator>COLEVAS, Dimitrios</creator><creator>COHEN, Marvin B</creator><creator>LORUSSO, Patricia M</creator><general>American Association for Cancer Research</general><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>7QL</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20050901</creationdate><title>Phase I Clinical Trial of BMS-247550, A Derivative of Epothilone B, Using Accelerated Titration 2B Design</title><author>GADGEEL, Shirish M ; WOZNIAK, Antoinette ; BOINPALLY, Ramesh R ; WIEGAND, Richard ; HEILBRUN, Lance K ; JAIN, Vikas ; PARCHMENT, Ralph ; COLEVAS, Dimitrios ; COHEN, Marvin B ; LORUSSO, Patricia M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c317t-2c74493fe8efcce771d9714324e1179b527a736774a306044f388607dc80e6813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Epothilone</topic><topic>Epothilones - administration & dosage</topic><topic>Epothilones - pharmacokinetics</topic><topic>Female</topic><topic>Humans</topic><topic>Infusions, Intravenous</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>MTD</topic><topic>Neoplasms - drug therapy</topic><topic>neutropenia</topic><topic>pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Phase I</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GADGEEL, Shirish M</creatorcontrib><creatorcontrib>WOZNIAK, Antoinette</creatorcontrib><creatorcontrib>BOINPALLY, Ramesh R</creatorcontrib><creatorcontrib>WIEGAND, Richard</creatorcontrib><creatorcontrib>HEILBRUN, Lance K</creatorcontrib><creatorcontrib>JAIN, Vikas</creatorcontrib><creatorcontrib>PARCHMENT, Ralph</creatorcontrib><creatorcontrib>COLEVAS, Dimitrios</creatorcontrib><creatorcontrib>COHEN, Marvin B</creatorcontrib><creatorcontrib>LORUSSO, Patricia M</creatorcontrib><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>Bacteriology Abstracts (Microbiology B)</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GADGEEL, Shirish M</au><au>WOZNIAK, Antoinette</au><au>BOINPALLY, Ramesh R</au><au>WIEGAND, Richard</au><au>HEILBRUN, Lance K</au><au>JAIN, Vikas</au><au>PARCHMENT, Ralph</au><au>COLEVAS, Dimitrios</au><au>COHEN, Marvin B</au><au>LORUSSO, Patricia M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase I Clinical Trial of BMS-247550, A Derivative of Epothilone B, Using Accelerated Titration 2B Design</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2005-09-01</date><risdate>2005</risdate><volume>11</volume><issue>17</issue><spage>6233</spage><epage>6239</epage><pages>6233-6239</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive
antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated
titration “2B” design, of BMS-247550 given as a 1-hour infusion every 3 weeks.
Experimental Design: Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles
(1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m 2 . All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists.
Results: First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m 2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m 2 . Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 56 mg/m 2 . Grade 1 to 2 peripheral neuropathy was also observed. Other grade 1 to 2 toxicities were myalgias, arthralgias, rash, hand/foot
syndrome, and mucositis. AUC and C max seemed proportional to the dose and the DLT. Development of neutropenia with BMS-247550 is related to the duration of drug
exposure above a threshold.
Conclusions: The maximum tolerated dose (MTD) of BMS-247550 is 40 mg/m 2 given every 3 weeks. Neutropenia is the DLT. The accelerated titration “2B” design may help in determining MTD with fewer
patients enrolled and more being treated closer to the MTD. However, the accelerated titration design did not seem to shorten
the study duration.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>16144926</pmid><doi>10.1158/1078-0432.CCR-05-0127</doi><tpages>7</tpages></addata></record> |
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| subjects | Adult Aged Aged, 80 and over Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Biological and medical sciences Epothilone Epothilones - administration & dosage Epothilones - pharmacokinetics Female Humans Infusions, Intravenous Male Maximum Tolerated Dose Medical sciences Middle Aged MTD Neoplasms - drug therapy neutropenia pharmacokinetics Pharmacology. Drug treatments Phase I |
| title | Phase I Clinical Trial of BMS-247550, A Derivative of Epothilone B, Using Accelerated Titration 2B Design |
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