Clofarabine and Low Dose Total Body Irradiation as a Preparative Regimen for Stem Cell Transplant in Leukemia.
Condition: Leukemia Lymphoblastic, Acute; Acute Myeloid Leukemia; Neoplasm Recurrent
MeSH terms: Leukemia; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 1

Summary: 
      Stem cell transplant is an important therapeutic option for pediatric patients with relapsed
      or refractory leukemia. Although, full myeloablative transplants are widely used for patients
      with acute leukemia, myeloablative chemo-radiotherapy may not be feasible in some specific
      settings. These settings include 1) patients with pre-existing health issues and organ
      toxicities; 2) patients who have relapsed post-ablative transplant and need a second stem
      cell transplant; and 3) leukemia patients with advanced disease who have been heavily
      pre-treated. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of
      significant antileukemic activity in addition to its possible immuno-suppressive properties.
      In this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in
      combination with total body irradiation that can achieve durable donor engraftment without
      causing excessive toxicity.
    

Detailed description: 
      Standard non-myeloablative regimens use Fludarabine and low dose total body irradiation (TBI)
      as pioneered by the Seattle group. Fludarabine is mainly used for its immuno-suppressive
      properties and has limited anti-leukemic effects. Since, the non-myeloablative and RIC
      regimens do not include intensive chemotherapy; relapse rates can be higher in RIC regimens
      compared to full myeloablative regimens. One way to improve overall survival in
      non-myeloablative / RIC setting is to add more effective anti-leukemia agents to prevent
      post-transplant relapses, without increasing TRM. Clofarabine, a new purine nucleoside
      anti-metabolite, has the advantage of significant antileukemic activity in addition to its
      possible immuno-suppressive properties. Combining Clofarabine with low dose TBI as a
      non-myeloablative preparative regimen may improve overall outcomes of SCT in advanced
      hematological malignancies. Therefore, in this study we plan to determine the maximum
      feasible dose (MFD) of Clofarabine in combination with 2Gy TBI that can achieve durable donor
      engraftment without causing excessive toxicity. The MFD determined from this pilot will be
      used in the next phase to study the outcomes after using this combination for SCT in this
      very high risk population.
    

Intervention name(s): Clofarabine; Total Body Irradiation; Stem Cell Transplantation; Cyclosporine; Mycophenolate Mofetil
Intervention type(s): Drug; Radiation; Other; Drug; Drug
Intervention description(s): Clofarabine will be given as an intravenous infusion over 2 hours on days -6 though -2. The dose of Clofarabine will be assigned at study entry (30, 40 or 52 mg/m2).; Low dose (2 Gy) TBI will be administered from a linear accelerator at ≤ 20 cGy/min on day "0" according to institutional guidelines.; Patients will be infused with 'unmanipulated' hematopoietic stem cells from a related or unrelated donor on day 0 of the treatment regimen according to institutional practice guidelines.; Cyclosporine is given IV based on body weight at:
Age ≤ 6 years old: 6 mg/kg IV QD. in divided doses (e.g. 2 mg/kg q8hrs).
Age > 6 years old: 3 mg/kg IV QD in divided doses (1.5mg/kg q12hrs)
Cyclosporine should be started on day -1 after completion of Clofarabine. Levels should be maintained between 300-400 ng/ml.; MMF will be at 15 mg/kg, based on adjusted body weight, q 8 hours (45 mg/kg/day; max.3g/day) PO, or IV if indicated, from the evening of day 0 (i.e. first dose 4-6 hours following stem cell infusion) to day +40 post-transplant. Oral doses will be rounded to the nearest 250 mg (capsules are 250 mg). MMF is also available in oral suspension form. MMF will be given until day +40 post transplant and then tapered by 10% per week to be discontinued by day +90.
Other intervention name(s): Clolar; Evoltra; TBI; SCT; Gengraf; Neoral; Sandimmune; MMF
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Clofarabine; Cyclosporins
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ALL; AML; Recurrence; Relapsed; Stem Cell Transplant; Non-myeloablative