Phase I Trial of VNP40101M (Cloretazine) in Children with Recurrent Brain Tumors: A Pediatric Brain Tumor Consortium Study
Purpose: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors. Experimental Design: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently in patient...
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| Veröffentlicht in: | Clinical cancer research 2008-02, Vol.14 (4), p.1124-1130 |
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| creator | Gururangan, Sridharan Turner, Christopher D Stewart, Clinton F O'Shaughnessy, Melinda Kocak, Mehmet Poussaint, Tina Young Phillips, Peter C Goldman, Stewart Packer, Roger Pollack, Ian F Blaney, Susan M Karsten, Verena Gerson, Stanton L Boyett, James M Friedman, Henry S Kun, Larry E |
| description | Purpose: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain
tumors.
Experimental Design: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently
in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum
II). Correlative studies included pharmacokinetics and measurement of O 6 -alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment.
Results: Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35
evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II.
Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum
I and II were 45 and 30 mg/m 2 /d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels
did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable
disease for a median of 45 weeks (range, 37-61+) after therapy.
Conclusions: The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m 2 /d in moderately pretreated and 30 mg/m 2 /d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks. |
| doi_str_mv | 10.1158/1078-0432.CCR-07-4242 |
| format | Article |
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tumors.
Experimental Design: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently
in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum
II). Correlative studies included pharmacokinetics and measurement of O 6 -alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment.
Results: Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35
evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II.
Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum
I and II were 45 and 30 mg/m 2 /d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels
did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable
disease for a median of 45 weeks (range, 37-61+) after therapy.
Conclusions: The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m 2 /d in moderately pretreated and 30 mg/m 2 /d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-07-4242</identifier><identifier>PMID: 18281546</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Adolescent ; Adult ; AGT ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - pharmacokinetics ; Area Under Curve ; Brain Neoplasms - drug therapy ; brain tumors ; Child ; Child, Preschool ; children ; Cloretazine ; Humans ; Hydrazines - administration & dosage ; Hydrazines - adverse effects ; Hydrazines - pharmacokinetics ; Infant ; Maximum Tolerated Dose ; Neoplasm Recurrence, Local - drug therapy ; phase I trial ; Sulfonamides - administration & dosage ; Sulfonamides - adverse effects ; Sulfonamides - pharmacokinetics</subject><ispartof>Clinical cancer research, 2008-02, Vol.14 (4), p.1124-1130</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-92da1473a762e1b4adbad28b458a1e27956bd252b7141d7dad540d2bc5bb179e3</citedby><cites>FETCH-LOGICAL-c418t-92da1473a762e1b4adbad28b458a1e27956bd252b7141d7dad540d2bc5bb179e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18281546$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gururangan, Sridharan</creatorcontrib><creatorcontrib>Turner, Christopher D</creatorcontrib><creatorcontrib>Stewart, Clinton F</creatorcontrib><creatorcontrib>O'Shaughnessy, Melinda</creatorcontrib><creatorcontrib>Kocak, Mehmet</creatorcontrib><creatorcontrib>Poussaint, Tina Young</creatorcontrib><creatorcontrib>Phillips, Peter C</creatorcontrib><creatorcontrib>Goldman, Stewart</creatorcontrib><creatorcontrib>Packer, Roger</creatorcontrib><creatorcontrib>Pollack, Ian F</creatorcontrib><creatorcontrib>Blaney, Susan M</creatorcontrib><creatorcontrib>Karsten, Verena</creatorcontrib><creatorcontrib>Gerson, Stanton L</creatorcontrib><creatorcontrib>Boyett, James M</creatorcontrib><creatorcontrib>Friedman, Henry S</creatorcontrib><creatorcontrib>Kun, Larry E</creatorcontrib><title>Phase I Trial of VNP40101M (Cloretazine) in Children with Recurrent Brain Tumors: A Pediatric Brain Tumor Consortium Study</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain
tumors.
Experimental Design: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently
in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum
II). Correlative studies included pharmacokinetics and measurement of O 6 -alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment.
Results: Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35
evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II.
Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum
I and II were 45 and 30 mg/m 2 /d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels
did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable
disease for a median of 45 weeks (range, 37-61+) after therapy.
Conclusions: The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m 2 /d in moderately pretreated and 30 mg/m 2 /d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.</description><subject>Adolescent</subject><subject>Adult</subject><subject>AGT</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Area Under Curve</subject><subject>Brain Neoplasms - drug therapy</subject><subject>brain tumors</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>children</subject><subject>Cloretazine</subject><subject>Humans</subject><subject>Hydrazines - administration & dosage</subject><subject>Hydrazines - adverse effects</subject><subject>Hydrazines - pharmacokinetics</subject><subject>Infant</subject><subject>Maximum Tolerated Dose</subject><subject>Neoplasm Recurrence, Local - drug therapy</subject><subject>phase I trial</subject><subject>Sulfonamides - administration & dosage</subject><subject>Sulfonamides - adverse effects</subject><subject>Sulfonamides - pharmacokinetics</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkEtPHDEMgKOqVaG0P6FVThU9DMSZZDLbG4ygRaJ0RReuUR5eJmgekMwIwa8nq92qPdmWP9vyR8hnYEcAsj4GpuqCiZIfNc11wVQhuOBvyD5IqYqSV_Jtzv8ye-RDSveMgQAm3pM9qHkNUlT75GXZmoT0gq5iMB0d1_T2aikYMPhFD5tujDiZlzDgNxoG2rSh8xEH-hSmll6jm2OuJnoaTe6u5n6M6Ts9oUv0wUwxuP87tBmHNMYpzD39M83--SN5tzZdwk-7eEBuzs9Wzc_i8vePi-bksnAC6qlYcG9AqNKoiiNYYbw1ntdWyNoAcrWQlfVccqvyd15546VgnlsnrQW1wPKAfN3ufYjj44xp0n1IDrvODDjOSXNWZytQZVBuQRfHlCKu9UMMvYnPGpjeSNcboXojVGfpmim9kZ7nvuwOzLZH_29qZzkDh1ugDXftU4ionRkcZnkJTXStBqFFvsBF-Qqcb4pf</recordid><startdate>20080215</startdate><enddate>20080215</enddate><creator>Gururangan, Sridharan</creator><creator>Turner, Christopher D</creator><creator>Stewart, Clinton F</creator><creator>O'Shaughnessy, Melinda</creator><creator>Kocak, Mehmet</creator><creator>Poussaint, Tina Young</creator><creator>Phillips, Peter C</creator><creator>Goldman, Stewart</creator><creator>Packer, Roger</creator><creator>Pollack, Ian F</creator><creator>Blaney, Susan M</creator><creator>Karsten, Verena</creator><creator>Gerson, Stanton L</creator><creator>Boyett, James M</creator><creator>Friedman, Henry S</creator><creator>Kun, Larry E</creator><general>American Association for Cancer Research</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>7TK</scope><scope>7TM</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20080215</creationdate><title>Phase I Trial of VNP40101M (Cloretazine) in Children with Recurrent Brain Tumors: A Pediatric Brain Tumor Consortium Study</title><author>Gururangan, Sridharan ; Turner, Christopher D ; Stewart, Clinton F ; O'Shaughnessy, Melinda ; Kocak, Mehmet ; Poussaint, Tina Young ; Phillips, Peter C ; Goldman, Stewart ; Packer, Roger ; Pollack, Ian F ; Blaney, Susan M ; Karsten, Verena ; Gerson, Stanton L ; Boyett, James M ; Friedman, Henry S ; Kun, Larry E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-92da1473a762e1b4adbad28b458a1e27956bd252b7141d7dad540d2bc5bb179e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>AGT</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Area Under Curve</topic><topic>Brain Neoplasms - drug therapy</topic><topic>brain tumors</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>children</topic><topic>Cloretazine</topic><topic>Humans</topic><topic>Hydrazines - administration & dosage</topic><topic>Hydrazines - adverse effects</topic><topic>Hydrazines - pharmacokinetics</topic><topic>Infant</topic><topic>Maximum Tolerated Dose</topic><topic>Neoplasm Recurrence, Local - drug therapy</topic><topic>phase I trial</topic><topic>Sulfonamides - administration & dosage</topic><topic>Sulfonamides - adverse effects</topic><topic>Sulfonamides - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gururangan, Sridharan</creatorcontrib><creatorcontrib>Turner, Christopher D</creatorcontrib><creatorcontrib>Stewart, Clinton F</creatorcontrib><creatorcontrib>O'Shaughnessy, Melinda</creatorcontrib><creatorcontrib>Kocak, Mehmet</creatorcontrib><creatorcontrib>Poussaint, Tina Young</creatorcontrib><creatorcontrib>Phillips, Peter C</creatorcontrib><creatorcontrib>Goldman, Stewart</creatorcontrib><creatorcontrib>Packer, Roger</creatorcontrib><creatorcontrib>Pollack, Ian F</creatorcontrib><creatorcontrib>Blaney, Susan M</creatorcontrib><creatorcontrib>Karsten, Verena</creatorcontrib><creatorcontrib>Gerson, Stanton L</creatorcontrib><creatorcontrib>Boyett, James M</creatorcontrib><creatorcontrib>Friedman, Henry S</creatorcontrib><creatorcontrib>Kun, Larry E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</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>Gururangan, Sridharan</au><au>Turner, Christopher D</au><au>Stewart, Clinton F</au><au>O'Shaughnessy, Melinda</au><au>Kocak, Mehmet</au><au>Poussaint, Tina Young</au><au>Phillips, Peter C</au><au>Goldman, Stewart</au><au>Packer, Roger</au><au>Pollack, Ian F</au><au>Blaney, Susan M</au><au>Karsten, Verena</au><au>Gerson, Stanton L</au><au>Boyett, James M</au><au>Friedman, Henry S</au><au>Kun, Larry E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase I Trial of VNP40101M (Cloretazine) in Children with Recurrent Brain Tumors: A Pediatric Brain Tumor Consortium Study</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2008-02-15</date><risdate>2008</risdate><volume>14</volume><issue>4</issue><spage>1124</spage><epage>1130</epage><pages>1124-1130</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain
tumors.
Experimental Design: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently
in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum
II). Correlative studies included pharmacokinetics and measurement of O 6 -alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment.
Results: Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35
evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II.
Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum
I and II were 45 and 30 mg/m 2 /d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels
did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable
disease for a median of 45 weeks (range, 37-61+) after therapy.
Conclusions: The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m 2 /d in moderately pretreated and 30 mg/m 2 /d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>18281546</pmid><doi>10.1158/1078-0432.CCR-07-4242</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Clinical cancer research, 2008-02, Vol.14 (4), p.1124-1130 |
| issn | 1078-0432 1557-3265 |
| language | eng |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adolescent Adult AGT Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Area Under Curve Brain Neoplasms - drug therapy brain tumors Child Child, Preschool children Cloretazine Humans Hydrazines - administration & dosage Hydrazines - adverse effects Hydrazines - pharmacokinetics Infant Maximum Tolerated Dose Neoplasm Recurrence, Local - drug therapy phase I trial Sulfonamides - administration & dosage Sulfonamides - adverse effects Sulfonamides - pharmacokinetics |
| title | Phase I Trial of VNP40101M (Cloretazine) in Children with Recurrent Brain Tumors: A Pediatric Brain Tumor Consortium Study |
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