Phase I/II Study of Continuous-Infusion Troxacitabine in Refractory Acute Myeloid Leukemia
Troxacitabine is a non-natural nucleoside analog with unique structural and metabolic features. Bolus intravenous (IV) troxacitabine regimens have shown significant activity in patients with refractory acute myeloid leukemia (AML) and preclinical data suggest that administration via continuous infus...
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Published in | Journal of clinical oncology Vol. 25; no. 1; pp. 10 - 15 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Baltimore, MD
American Society of Clinical Oncology
01.01.2007
Lippincott Williams & Wilkins |
Subjects | |
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Abstract | Troxacitabine is a non-natural nucleoside analog with unique structural and metabolic features. Bolus intravenous (IV) troxacitabine regimens have shown significant activity in patients with refractory acute myeloid leukemia (AML) and preclinical data suggest that administration via continuous infusion may result in enhanced antitumor activity.
Patients with refractory AML initially received troxacitabine 10.1 mg/m2 by continuous IV infusion (CIVI) for 48 hours. Infusion duration and daily dose were increased in subsequent patient cohorts.
Forty-eight patients, median age 58 years (range, 21 to 81 years), were treated. Dose-limiting toxicities were mucositis and hand-foot syndrome, and 12.0 mg/m2/d for 5 days was established as the maximum-tolerated dose. Seven patients (15%) achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), with a median survival among responders of 12 months. Steady-state concentrations of troxacitabine were found to be linearly and inversely proportionally related to calculated creatinine clearance at doses of 10.1 and 12.0 mg/m2/d. All patients responding to troxacitabine had steady-state serum drug concentration of more than approximately 80 ng/mL. In 27 patients achieving target troxacitabine plasma concentrations (ie, approximately 80 ng/mL) the CR + CRp rate was 26%.
Troxacitabine administered as a CIVI allows a significant increase in dose-intensity in comparison to IV bolus regimens, has antileukemic activity, and warrants additional investigation in patients with refractory AML. The recommended phase II study dose is 12.0 mg/m2 daily CIVI for 5 days. |
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AbstractList | Troxacitabine is a non-natural nucleoside analog with unique structural and metabolic features. Bolus intravenous (IV) troxacitabine regimens have shown significant activity in patients with refractory acute myeloid leukemia (AML) and preclinical data suggest that administration via continuous infusion may result in enhanced antitumor activity.
Patients with refractory AML initially received troxacitabine 10.1 mg/m2 by continuous IV infusion (CIVI) for 48 hours. Infusion duration and daily dose were increased in subsequent patient cohorts.
Forty-eight patients, median age 58 years (range, 21 to 81 years), were treated. Dose-limiting toxicities were mucositis and hand-foot syndrome, and 12.0 mg/m2/d for 5 days was established as the maximum-tolerated dose. Seven patients (15%) achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), with a median survival among responders of 12 months. Steady-state concentrations of troxacitabine were found to be linearly and inversely proportionally related to calculated creatinine clearance at doses of 10.1 and 12.0 mg/m2/d. All patients responding to troxacitabine had steady-state serum drug concentration of more than approximately 80 ng/mL. In 27 patients achieving target troxacitabine plasma concentrations (ie, approximately 80 ng/mL) the CR + CRp rate was 26%.
Troxacitabine administered as a CIVI allows a significant increase in dose-intensity in comparison to IV bolus regimens, has antileukemic activity, and warrants additional investigation in patients with refractory AML. The recommended phase II study dose is 12.0 mg/m2 daily CIVI for 5 days. |
Author | Stefan Faderl Ellen K. Ritchie S. Lani Park Gail J. Roboz Michael J. Kelner Tania J. Curcio Hagop M. Kantarjian Farhad Ravandi Sandra Allen-Bard Meredith A. Wilkes Eric J. Feldman Francis J. Giles |
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Keywords | Antineoplastic agent Treatment resistance Cancerology Treatment Troxacitabine Perfusion Phase II trial Phase I trial Nucleoside analog Malignant hemopathy Acute myelocytic leukemia |
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SubjectTerms | Adolescent Adult Aged Aged, 80 and over Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Biological and medical sciences Cytosine - administration & dosage Cytosine - analogs & derivatives Cytosine - pharmacokinetics Dioxolanes - administration & dosage Dioxolanes - pharmacokinetics Female Hematologic and hematopoietic diseases Humans Infusions, Intravenous Leukemia, Myeloid, Acute - drug therapy Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical sciences Middle Aged Time Factors Treatment Outcome Tumors |
Title | Phase I/II Study of Continuous-Infusion Troxacitabine in Refractory Acute Myeloid Leukemia |
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