TY - JOUR
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
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
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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U2 - 10.1200/JCO.2004.07.111
DO - 10.1200/JCO.2004.07.111
M3 - Article
C2 - 15084615
AN - SCOPUS:2342618217
SN - 0732-183X
VL - 22
SP - 1413
EP - 1419
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 8
ER -