Clofarabine, Cytarabine and Mitoxantrone (CLAM) for Relapsed or Refractory AML
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 2

Summary: 
      The study aims to evaluate the efficacy of the regimen CLAM in relapsed or refractory AML
      when used as first salvage for patients to relapse or fail after standard treatment with
      daunorubicin/cytarabine induction.
    

Detailed description: 
      Clofarabine, a second generation purine nucleoside analog, has been evaluated in several
      studies in relapsed AML.[1-3] Safety and dosages of clorafabine have already been determined
      in previous phase I/II studies. A demonstrable complete remission rate of up to 40% to 50%
      was shown in relapsed or refractory AML.[4-6] Since 2009, Clofarabine (40mg/m2/day for 5
      days) in combination with high-dose cytarabine (2g/m2/day for 5 days) (CLARA) was adopted as
      the re-induction protocol for relapsed or refractory patients with AML at the Department of
      Medicine, Queen Mary Hospital. We have shown that this protocol is safe, tolerable and
      effective for relapsed AML. A recent updated analysis (Gill H et al., unpublished) showed a
      completed response rate of 50.8%. With the CLARA regimen, all patients (N=60) developed grade
      3/4 neutropenia and thrombocytopenia. 8% developed grade 3/4 hepatotoxicity and 40% developed
      febrile neutropenia with clinical sepsis. There is increasing evidence to show that
      clofarabine is safe and efficacious when combined with the anthracyclines idarubicin or
      daunorubicin.7,8 In this prospective study, we combine clofarabine and cytarabine (Ara-C)
      with the topoisomerase II inhibitor mitoxantrone. In this protocol, the dosages of
      clofarabine and cytarabine will be reduced to 30mg/m2/day and 750mg/m2/day respectively,
      comparable to most clinical trials. In our previous publication of experience with the use of
      CLARA by Tse et al and Leung et al, clofarabine at 40mg/m2/day for 5 days was combined with
      high-dose cytarabine at 2g/m2/day.[5,6] The regimen was shown to be safe. The combination of
      clofarabine with anthracyclines has been evaluated. Mathiesen at al evaluated the CIA regimen
      comprising clofarabine at 20mg/m2/day from day 1 to day 5, idarubicin at 10mg/m2/day from day
      1 to day 3 and cytarabine at 1g/m2/day from day 1 to day 5.[7] Abbie et al investigated the
      regimen comprising Clofarabine at 20mg/m2/day or 25mg/m2/day for 5 days in combination with
      mitoxantrone and etoposide.7 Based on the clinical trials and our extensive experience with
      the use of CLARA, the dosages of clofarabine in CLAM was determined. With the significant
      reduction in the dose of cytarabine to 750mg/m2/day for 5 days in CLAM, the dose of
      clofarabine was chosen at 30mg/m2/day for 5 days with the aim to maintain the efficacy seen
      with CLARA. The aim of this combination is to maintain or improve treatment efficacy seen
      with a lower treatment-related toxicity via dose reduction of clofarabine and cytarabine
      compared to CLARA. CLAM is expected to be safe and tolerable especially when used as first
      salvage in patient with a ECOG performance status of 0 or 1. The regimen CLAM has been
      approved by the institutional review board of Queen Mary Hospital/University of Hong Kong. In
      a pilot study, 4 patients used the regimen. 2 patients achieved a complete remission.
      Cardiotoxicity was not seen. Grade 3/4 hepatotoxicity was not seen. There were no
      treatment-related mortality observed. CLAM was shown to be safe and with manageable toxicity
      profile. In addition, less myeloid toxicity is expected during consolidation as patients who
      achieve a remission will have better marrow reserve when compared to those at relapse.
      Patients will have their cardiac, liver and renal function and performance status evaluated
      continuously and patients with cardiac dysfunction, significantly impaired renal or liver
      function and ECOG performance status of 2 or above will be excluded. Thus consolidation with
      the same dose as with induction is expected to be safe and tolerable.

      The study aims to evaluate the efficacy of the regimen CLAM in relapsed or refractory AML
      when used as first salvage for patients to relapse or fail after standard treatment with
      daunorubicin/cytarabine induction. We aim to improve treatment efficacy at a more tolerable
      dose of clofarabine and cytarabine compared to CLARA.
    

Intervention name(s): Clofarabine, AraC, mitoxantrone (CLAM)
Intervention type(s): Drug
Intervention description(s): The combination of clofarabine, cytarabine (Ara-C) and mitoxantrone will be used in patients with AML in first relapse or after failure of first salvage
Other intervention name(s): CLAM
Intervention MeSH terms: Mitoxantrone; Clofarabine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Clofarabine; Acute Myeloid Leukemia