Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors

A pediatric brain tumor consortium study

Sridharan Gururangan, Christopher D. Turner, Clinton F. Stewart, Melinda O'Shaughnessy, Mehmet Kocak, Tina Young Poussaint, Peter C. Phillips, Stewart Goldman, Roger Packer, Ian F. Pollack, Susan M. Blaney, Verena Karsten, Stanton L. Gerson, James M. Boyett, Henry S. Friedman, Larry E. Kun

Research output: Contribution to journalArticle

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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 O6-alkylguanine-DNA alkyl transferase levels in peripheral bloodmononuclear 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/m2/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 VNP40101Mfor phase II studies in children with brain tumors is 45 mg/m 2/d in moderately pretreated and 30 mg/m2/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.

Original languageEnglish (US)
Pages (from-to)1124-1130
Number of pages7
JournalClinical Cancer Research
Volume14
Issue number4
DOIs
StatePublished - Feb 15 2008
Externally publishedYes

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Brain Neoplasms
Pediatrics
Transferases
Pharmacokinetics
Maximum Tolerated Dose
Alkylating Agents
DNA
Therapeutics
laromustine
Half-Life
Blood Cells
Research Design

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors : A pediatric brain tumor consortium study. / 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.

In: Clinical Cancer Research, Vol. 14, No. 4, 15.02.2008, p. 1124-1130.

Research output: Contribution to journalArticle

Gururangan, S, Turner, CD, Stewart, CF, O'Shaughnessy, M, Kocak, M, Poussaint, TY, Phillips, PC, Goldman, S, Packer, R, Pollack, IF, Blaney, SM, Karsten, V, Gerson, SL, Boyett, JM, Friedman, HS & Kun, LE 2008, 'Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: A pediatric brain tumor consortium study', Clinical Cancer Research, vol. 14, no. 4, pp. 1124-1130. https://doi.org/10.1158/1078-0432.CCR-07-4242
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. / Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors : A pediatric brain tumor consortium study. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 4. pp. 1124-1130.
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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 O6-alkylguanine-DNA alkyl transferase levels in peripheral bloodmononuclear 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/m2/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 VNP40101Mfor phase II studies in children with brain tumors is 45 mg/m 2/d in moderately pretreated and 30 mg/m2/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.",
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T1 - Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors

T2 - A pediatric brain tumor consortium study

AU - Gururangan, Sridharan

AU - Turner, Christopher D.

AU - Stewart, Clinton F.

AU - O'Shaughnessy, Melinda

AU - Kocak, Mehmet

AU - Poussaint, Tina Young

AU - Phillips, Peter C.

AU - Goldman, Stewart

AU - Packer, Roger

AU - Pollack, Ian F.

AU - Blaney, Susan M.

AU - Karsten, Verena

AU - Gerson, Stanton L.

AU - Boyett, James M.

AU - Friedman, Henry S.

AU - Kun, Larry E.

PY - 2008/2/15

Y1 - 2008/2/15

N2 - 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 O6-alkylguanine-DNA alkyl transferase levels in peripheral bloodmononuclear 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/m2/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 VNP40101Mfor phase II studies in children with brain tumors is 45 mg/m 2/d in moderately pretreated and 30 mg/m2/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.

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