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Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia.
Blood. 1993 Mar 01; 81(5):1146-51.Blood

Abstract

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to-moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

Authors+Show Affiliations

Department of Hematology, University of Texas, M.D. Anderson Cancer Center, Houston 77030.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8382970

Citation

Kantarjian, H M., et al. "Phase I Study of Topotecan, a New Topoisomerase I Inhibitor, in Patients With Refractory or Relapsed Acute Leukemia." Blood, vol. 81, no. 5, 1993, pp. 1146-51.
Kantarjian HM, Beran M, Ellis A, et al. Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. Blood. 1993;81(5):1146-51.
Kantarjian, H. M., Beran, M., Ellis, A., Zwelling, L., O'Brien, S., Cazenave, L., Koller, C., Rios, M. B., Plunkett, W., & Keating, M. J. (1993). Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. Blood, 81(5), 1146-51.
Kantarjian HM, et al. Phase I Study of Topotecan, a New Topoisomerase I Inhibitor, in Patients With Refractory or Relapsed Acute Leukemia. Blood. 1993 Mar 1;81(5):1146-51. PubMed PMID: 8382970.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. A1 - Kantarjian,H M, AU - Beran,M, AU - Ellis,A, AU - Zwelling,L, AU - O'Brien,S, AU - Cazenave,L, AU - Koller,C, AU - Rios,M B, AU - Plunkett,W, AU - Keating,M J, PY - 1993/3/1/pubmed PY - 1993/3/1/medline PY - 1993/3/1/entrez SP - 1146 EP - 51 JF - Blood JO - Blood VL - 81 IS - 5 N2 - The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to-moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/8382970/Phase_I_study_of_Topotecan_a_new_topoisomerase_I_inhibitor_in_patients_with_refractory_or_relapsed_acute_leukemia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)85445-7 DB - PRIME DP - Unbound Medicine ER -