Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia

N. Vey, H. M. Kantarjian, H. Tran, M. Beran, S. O'Brien, C. Bivins, F. Giles, J. Cortes, B. Cheson, S. Arbuck, E. Estey

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20 Scopus citations

Abstract

Purpose: Topoisomerase 1 inhibitors have shown promising anti leukemic activity in acute myelogenous leukemia (AML) and myelodysplastic syndrome. In this phase 1 study, we investigated the toxicity profile, pharmacokinetics, and activity of a prolonged continuous infusion schedule of the colloidal dispersion formulation of 9-amino-camptothecin (9-AC/CD) in patients with acute leukemia. Patents and methods: Patients with refractory or relapsed AML, acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia in blastic phase (CML-BP) were included in the study. Eligibility criteria were age greater than 15 years, performance status of 2 or better, creatinine < 1.5 mg/dl, and bilirubin < 1.5 mg/dl. 9-AC/CD was given as a continuous intravenous infusion over seven days every three to four weeks. The starting dose was 0.2 mg/m2/d (1.4 mg/m2/course). Courses were given every three to four weeks according to toxicity and anti leukemic efficacy. This phase I study used the classical 3 + 3 design. The dose was escalated by 50%, until grade 1 toxicity was observed, and then by 30% to 35% until the dose limiting toxicity was defined. At the maximal tolerated dose (MTD). 8 to 10 patients were planned to be treated to better define the toxicity and early-activity profiles. Results: Thirty-nine patients (AML thirty-six patients: ALL two patients: CML-BP one patient), median age 56 years were treated. Severe mucositis was the dose limiting toxicity: it occurred in three of six patients treated at a dose of 1.6 mg/m2/d. The MTD was defined as 1.4 mg/m2 day by the phase I design. Upon expansion of the number of patients, 3 of 10 patients had grade 4 mucositis and 1 of 10 patients had grade 3 diarrhea. Nausea and vomiting were uncommon. No complete or partial remission was observed in 37 evaluable patients. However, 9-AC/CD exhibited antileukemic activity, as reflected by the finding of marrow hypoplasia on day 14 in 46% of the patients. Average steady-slate concentration of 9-AC lactone was close to 10 nmol/l, and the of 9-AC lactone area under curve (AUC) was 1409 ± 705 nmol/l · hr. Conclusion: The MTD of 9-AC/CD given as a seven-day continuous infusion was 1.4 mg/m2/d (9.8 mg/m2/course) in patients with acute leukemia. This represents three to fourfold dose escalation compared with the MTD of 9-AC given as shorter continuous infusion (three days) in patients with solid tumors. Future studies will determine the activity of prolonged administration of 9-AC/CD in patients with better prognosis acute leukemia.

Original languageEnglish (US)
Pages (from-to)577-583
Number of pages7
JournalAnnals of Oncology
Volume10
Issue number5
DOIs
StatePublished - Jul 12 1999
Externally publishedYes

Keywords

  • 9-aminocamptothecin
  • Acute leukemia
  • Phase I/clinical trial
  • Topoisomerase I inhibitors

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Vey, N., Kantarjian, H. M., Tran, H., Beran, M., O'Brien, S., Bivins, C., Giles, F., Cortes, J., Cheson, B., Arbuck, S., & Estey, E. (1999). Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia. Annals of Oncology, 10(5), 577-583. https://doi.org/10.1023/A:1026406920321