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Phase I and pharmacokinetic study of elacytarabine, a novel 5′-elaidic acid derivative of cytarabine, in adults with refractory hematological malignancies

Leukemia volume 26, pages 1686–1689 (2012)Cite this article

Subjects

A total of 77 patients (median age 60–63 years; 69 with AML; 37, schedule A; 40, schedule B) were enrolled. The schedules were comparable with respect to patient characteristics. A total of 127 elacytarabine courses were administered: 59 (mean/patient 1.6) in schedule A, 68 (mean/patient 1.7) in schedule B. Of the total, 21 (27.3%) patients died within 30 days and 29 (37.6%) within 60 days with active disease and infection. No death was attributed to elacytarabine and death rate was not affected by the schedule. The DLT (grade 3 hyperbilirubinemia) occurred in two patients at the 2500 mg/m2 per day in both schedules after assessment of seven dose levels in schedule A and eight in schedule B. For patients on schedule A, the events lasted for 5 and 12 days. The latter patient also had aspartate aminotrasferase elevation (grade 4) for 5 days and an increase of alkaline phosphatase(changed to grade 2 from grade 1 at study entry), but this rise did not last more than 7 days and was not dose limiting. For patients in schedule B, the two DLTs lasted for 3 and 13 days. All DLTs were fully reversible and liver function normalized within days after discontinuation of elacytarabine. The MTD for both schedules was exceeded at 2500 mg/m2 per day and thus 11 patients in schedule A and 10 in schedule B were accrued at 2000 mg/m2 per day, which was established as the recommended dose for phase II for both schedules. The most common grade 3/4 adverse events (AE) were infections, anemia, fatigue and elevations of liver function tests. Nausea, constipation and diarrhea were reported in more than 35% of patients, but mostly of lower grade (1–2) intensity. The toxicities observed were manageable and transient. No infusion related reactions were observed.

Anti-leukemia activity (complete remission (CR) or complete remission with incomplete platelet recovery (CRp)) was observed in 6/57 (11%) of patients receiving ⩾875 mg/m2 per day of elacytarabine; 5/29 (17%) in schedule B and 1/28 (4%) in schedule A. In schedule B, CR or CRp, was observed in three male and two female patients ranging in age from 24 to 78 years; three had previously been treated with, and were refractory to, ara-C-containing regimens and undergone stem cell transplantation (SCT). One 24-year-old female entered the study with refractory/relapsed AML after multiple regimens, including ara-C/daunorubicin, SCT, Flag-IDA, azacitidine and ara-C/idarubicin/gemtuzumab, and an investigational drug. The patient had attained CR only after the latter. This patient attained CR after the first course of elacytarabine (only 3 days dosing at 2000 mg/m2 per day). The remission was maintained through two consolidation courses of elacytarabine therapy when the patient was removed from study to receive a SCT. At study end the patient had been in remission for 16.5 weeks. In schedule B, the median duration of remission was 7 weeks (range 3–16.5+ weeks). A second patient underwent a second SCT after obtaining a remission with elacytarabine. The median time from start of treatment to remission was 21 days (range 20–28 days). In schedule A, complete remission (CRp) was observed in a 92-year-old man who had received decitabine/valproic acid as well as imatinib in previous treatment regimens. The remission was attained after one course of treatment (dose 2000 mg/m2 per day). Partial remission (PR) was attained in two patients with AML, one in each schedule. None of the patients receiving elacytarabine at doses below 875 mg/m2 per day attained remission. Disease was stable after the first treatment course in 12 patients in schedule A (10 AML) and 12 patients in schedule B (all AML).

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Author notes

  1. B Nilsson: Deceased.

Authors and Affiliations

  1. HRB Clinical Research Facilities, National University of Ireland Galway and Trinity College Dublin, Dublin, Ireland

    F J Giles

  2. Department of Hematology, Institut Paoli-Calmettes, Marseille, France

    N Vey & T Prebet

  3. Division of Cellular Therapy, Duke University Hospital, Durham, NC, USA

    D Rizzieri

  4. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    F Ravandi, G Borthakur & S O'Brien

  5. Clavis Pharma, Oslo, Norway

    T F Jacobsen, S Hagen & B Nilsson

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Correspondence to F J Giles.

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Competing interests

FJ Giles, N Vey, D Rizzieri and S O'Brien have received research funding from Clavis Pharma. TF Jacobsen, S Hagen and B Nilsson are/were Clavis Pharma employees.

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Giles, F., Vey, N., Rizzieri, D. et al. Phase I and pharmacokinetic study of elacytarabine, a novel 5′-elaidic acid derivative of cytarabine, in adults with refractory hematological malignancies. Leukemia 26, 1686–1689 (2012). https://doi.org/10.1038/leu.2012.1

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