Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers

Hagop M. Kantarjian, Varsha Gandhi, Peter Kozuch, Stefan Faderl, Francis Giles, Jorge Cortes, Susan O'Brien, Nuhad Ibrahim, Fadlo Khuri, Min Du, Mary Beth Rios, Sima Jeha, Peter McLaughlin, William Plunkett, Michael Keating

Research output: Contribution to journalArticle

Abstract

Purpose: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia. Patients and Methods: The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia. Results: The starting dose of clofarabine (15 mg/m2) was myelosuppressive, requiring several dose de-escalations to 2 mg/m2, the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m2, with several escalations to 55 mg/m2. The DLT was reversible hepatotoxicity at 55 mg/m2. The recommended dose for acute leukemia phase II studies was 40 mg/m2. Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m2, the median plasma clofarabine level was 1.5 μmol/L (range, 0.42 to 3.2 μmol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate. Conclusion: This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m2 for solid tumors, the DLT being myelosuppression; and 40 mg/m2 for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.

Original languageEnglish (US)
Pages (from-to)1167-1173
Number of pages7
JournalJournal of Clinical Oncology
Volume21
Issue number6
DOIs
StatePublished - Mar 15 2003
Externally publishedYes

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Clinical Pharmacology
Leukemia
Maximum Tolerated Dose
Neoplasms
clofarabine
Clinical Studies
Blood Platelets
Pharmacokinetics
Bone Marrow

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. / Kantarjian, Hagop M.; Gandhi, Varsha; Kozuch, Peter; Faderl, Stefan; Giles, Francis; Cortes, Jorge; O'Brien, Susan; Ibrahim, Nuhad; Khuri, Fadlo; Du, Min; Rios, Mary Beth; Jeha, Sima; McLaughlin, Peter; Plunkett, William; Keating, Michael.

In: Journal of Clinical Oncology, Vol. 21, No. 6, 15.03.2003, p. 1167-1173.

Research output: Contribution to journalArticle

Kantarjian, HM, Gandhi, V, Kozuch, P, Faderl, S, Giles, F, Cortes, J, O'Brien, S, Ibrahim, N, Khuri, F, Du, M, Rios, MB, Jeha, S, McLaughlin, P, Plunkett, W & Keating, M 2003, 'Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers', Journal of Clinical Oncology, vol. 21, no. 6, pp. 1167-1173. https://doi.org/10.1200/JCO.2003.04.031
Kantarjian, Hagop M. ; Gandhi, Varsha ; Kozuch, Peter ; Faderl, Stefan ; Giles, Francis ; Cortes, Jorge ; O'Brien, Susan ; Ibrahim, Nuhad ; Khuri, Fadlo ; Du, Min ; Rios, Mary Beth ; Jeha, Sima ; McLaughlin, Peter ; Plunkett, William ; Keating, Michael. / Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. In: Journal of Clinical Oncology. 2003 ; Vol. 21, No. 6. pp. 1167-1173.
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T1 - Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers

AU - Kantarjian, Hagop M.

AU - Gandhi, Varsha

AU - Kozuch, Peter

AU - Faderl, Stefan

AU - Giles, Francis

AU - Cortes, Jorge

AU - O'Brien, Susan

AU - Ibrahim, Nuhad

AU - Khuri, Fadlo

AU - Du, Min

AU - Rios, Mary Beth

AU - Jeha, Sima

AU - McLaughlin, Peter

AU - Plunkett, William

AU - Keating, Michael

PY - 2003/3/15

Y1 - 2003/3/15

N2 - Purpose: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia. Patients and Methods: The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia. Results: The starting dose of clofarabine (15 mg/m2) was myelosuppressive, requiring several dose de-escalations to 2 mg/m2, the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m2, with several escalations to 55 mg/m2. The DLT was reversible hepatotoxicity at 55 mg/m2. The recommended dose for acute leukemia phase II studies was 40 mg/m2. Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m2, the median plasma clofarabine level was 1.5 μmol/L (range, 0.42 to 3.2 μmol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate. Conclusion: This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m2 for solid tumors, the DLT being myelosuppression; and 40 mg/m2 for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.

AB - Purpose: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia. Patients and Methods: The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia. Results: The starting dose of clofarabine (15 mg/m2) was myelosuppressive, requiring several dose de-escalations to 2 mg/m2, the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m2, with several escalations to 55 mg/m2. The DLT was reversible hepatotoxicity at 55 mg/m2. The recommended dose for acute leukemia phase II studies was 40 mg/m2. Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m2, the median plasma clofarabine level was 1.5 μmol/L (range, 0.42 to 3.2 μmol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate. Conclusion: This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m2 for solid tumors, the DLT being myelosuppression; and 40 mg/m2 for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.

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