Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia

Francis J. Giles, Jorge E. Cortes, Deborah A. Thomas, Guillermo Garcia-Manero, Stephan Faderl, Sima Jeha, Robert L. De Jager, Hagop M. Kantarjian

Research output: Contribution to journalArticle

Abstract

Purpose: DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP). Experimental Design: DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m2/day for 5 days (3.0 mg/m2/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy. Results: Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, occurring in two of two patients treated at 1.35 mg/m2/day for 5 days, two of three treated at 1.2 mg/m2/day for 5 days, and one of six treated at 0.9 mg/m2/day for 7 days. The recommended Phase II dose was 0.9 mg/m2/day for 5 days. The pharmacokinetics of DX-8951 was linear and well fit by a two-compartment model. Conclusions: Phase II studies are warranted to further define the activity of DX-8951f in patients with hematological malignancies.

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Camptothecin
Appointments and Schedules
Leukemia
Pharmacokinetics
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Topoisomerase I Inhibitors
Stomatitis
SCID Mice
exatecan
Hematologic Neoplasms
Research Design

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Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia. / Giles, Francis J.; Cortes, Jorge E.; Thomas, Deborah A.; Garcia-Manero, Guillermo; Faderl, Stephan; Jeha, Sima; De Jager, Robert L.; Kantarjian, Hagop M.

In: Clinical Cancer Research, Vol. 8, No. 7, 01.01.2002, p. 2134-2141.

Research output: Contribution to journalArticle

Giles, FJ, Cortes, JE, Thomas, DA, Garcia-Manero, G, Faderl, S, Jeha, S, De Jager, RL & Kantarjian, HM 2002, 'Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia', Clinical Cancer Research, vol. 8, no. 7, pp. 2134-2141.
Giles, Francis J. ; Cortes, Jorge E. ; Thomas, Deborah A. ; Garcia-Manero, Guillermo ; Faderl, Stephan ; Jeha, Sima ; De Jager, Robert L. ; Kantarjian, Hagop M. / Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia. In: Clinical Cancer Research. 2002 ; Vol. 8, No. 7. pp. 2134-2141.
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abstract = "Purpose: DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP). Experimental Design: DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m2/day for 5 days (3.0 mg/m2/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy. Results: Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, occurring in two of two patients treated at 1.35 mg/m2/day for 5 days, two of three treated at 1.2 mg/m2/day for 5 days, and one of six treated at 0.9 mg/m2/day for 7 days. The recommended Phase II dose was 0.9 mg/m2/day for 5 days. The pharmacokinetics of DX-8951 was linear and well fit by a two-compartment model. Conclusions: Phase II studies are warranted to further define the activity of DX-8951f in patients with hematological malignancies.",
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T1 - Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia

AU - Giles, Francis J.

AU - Cortes, Jorge E.

AU - Thomas, Deborah A.

AU - Garcia-Manero, Guillermo

AU - Faderl, Stephan

AU - Jeha, Sima

AU - De Jager, Robert L.

AU - Kantarjian, Hagop M.

PY - 2002/1/1

Y1 - 2002/1/1

N2 - Purpose: DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP). Experimental Design: DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m2/day for 5 days (3.0 mg/m2/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy. Results: Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, occurring in two of two patients treated at 1.35 mg/m2/day for 5 days, two of three treated at 1.2 mg/m2/day for 5 days, and one of six treated at 0.9 mg/m2/day for 7 days. The recommended Phase II dose was 0.9 mg/m2/day for 5 days. The pharmacokinetics of DX-8951 was linear and well fit by a two-compartment model. Conclusions: Phase II studies are warranted to further define the activity of DX-8951f in patients with hematological malignancies.

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