Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors: A pediatric oncology group study

Victor M. Aquino, Steve D. Weittnan, Naomi J. Winick, Susan Blaney, Wayne L. Furman, James L. Kepner, Peter Bonate, Mark Krailo, Wenchun Qu, Mark Bernstein

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. Patients and Methods: Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m2 Cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m 2 and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. Results: Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m2 in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m2. Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m2. This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curvelast was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. Conclusion: The recommended dose of tirapazamine given with 1,500 mg/m2 of cyclophosphamide once every 3 weeks is 325 mg/m 2. Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.

Original languageEnglish (US)
Pages (from-to)1413-1419
Number of pages7
JournalJournal of Clinical Oncology
Volume22
Issue number8
DOIs
StatePublished - 2004

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tirapazamine
Cyclophosphamide
Pediatrics
Neoplasms
Pharmacokinetics
Neutropenia
Neuroblastoma
Bone Marrow
Mesna
Maximum Tolerated Dose
Rhabdomyosarcoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors : A pediatric oncology group study. / Aquino, Victor M.; Weittnan, Steve D.; Winick, Naomi J.; Blaney, Susan; Furman, Wayne L.; Kepner, James L.; Bonate, Peter; Krailo, Mark; Qu, Wenchun; Bernstein, Mark.

In: Journal of Clinical Oncology, Vol. 22, No. 8, 2004, p. 1413-1419.

Research output: Contribution to journalArticle

Aquino, Victor M. ; Weittnan, Steve D. ; Winick, Naomi J. ; Blaney, Susan ; Furman, Wayne L. ; Kepner, James L. ; Bonate, Peter ; Krailo, Mark ; Qu, Wenchun ; Bernstein, Mark. / Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors : A pediatric oncology group study. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 8. pp. 1413-1419.
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abstract = "Purpose: To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. Patients and Methods: Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m2 Cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m 2 and was increased by 30{\%} in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. Results: Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m2 in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m2. Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m2. This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curvelast was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. Conclusion: The recommended dose of tirapazamine given with 1,500 mg/m2 of cyclophosphamide once every 3 weeks is 325 mg/m 2. Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.",
author = "Aquino, {Victor M.} and Weittnan, {Steve D.} and Winick, {Naomi J.} and Susan Blaney and Furman, {Wayne L.} and Kepner, {James L.} and Peter Bonate and Mark Krailo and Wenchun Qu and Mark Bernstein",
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T1 - Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors

T2 - A pediatric oncology group study

AU - Aquino, Victor M.

AU - Weittnan, Steve D.

AU - Winick, Naomi J.

AU - Blaney, Susan

AU - Furman, Wayne L.

AU - Kepner, James L.

AU - Bonate, Peter

AU - Krailo, Mark

AU - Qu, Wenchun

AU - Bernstein, Mark

PY - 2004

Y1 - 2004

N2 - Purpose: To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. Patients and Methods: Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m2 Cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m 2 and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. Results: Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m2 in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m2. Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m2. This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curvelast was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. Conclusion: The recommended dose of tirapazamine given with 1,500 mg/m2 of cyclophosphamide once every 3 weeks is 325 mg/m 2. Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.

AB - Purpose: To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. Patients and Methods: Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m2 Cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m 2 and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. Results: Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m2 in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m2. Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m2. This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curvelast was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. Conclusion: The recommended dose of tirapazamine given with 1,500 mg/m2 of cyclophosphamide once every 3 weeks is 325 mg/m 2. Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.

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