Clofarabine, Melphalan, and Thiotepa Followed By a Donor Stem Cell Transplant in Treating Patients With High-Risk and/or Advanced Hematologic Cancer or Other Disease
Condition: Graft Versus Host Disease; Leukemia; Myelodysplastic Syndromes
MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Graft vs Host Disease; Syndrome
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Giving chemotherapy, such as clofarabine, melphalan, and thiotepa, before a donor
      stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop
      the patient's immune system from rejecting the donor's stem cells. When the healthy stem
      cells from a donor are infused into the patient they may help the patient's bone marrow make
      stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted
      cells from a donor can also make an immune response against the body's normal cells. Giving
      tacrolimus and mycophenolate mofetil before the transplant may stop this from happening.

      PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine when
      given together with melphalan and thiotepa, followed by a donor stem cell transplant and to
      see how well it works in treating patients with high-risk and/or advanced hematologic cancer
      or other disease.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the maximum tolerated dose of clofarabine when administered with melphalan and
           thiotepa followed by allogeneic stem cell transplantation in patients with high-risk
           and/or advanced hematologic malignancies. (Phase I)

        -  Determine the 1-year disease-free survival of patients treated with this regimen. (Phase
           II)

        -  Determine the efficacy of this regimen, in terms of antileukemic potential and relapse
           rate, in these patients.

      Secondary

        -  Evaluate the incidence and severity of nonhematologic toxicity of this regimen in these
           patients.

        -  Evaluate the incidence and severity of graft-versus-host disease in patients treated
           with this regimen.

      OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by an open-label,
      phase II study. Patients are stratified according to HLA-compatible donor type (related vs
      unrelated).

        -  Cytoreductive therapy: Patients receive clofarabine IV over 2 hours once daily on days
           -9 to -5, thiotepa IV over 4 hours on day -4, and melphalan IV over 30 minutes once
           daily on days -3 and -2.

      Cohorts of 3-6 patients receive escalating doses of clofarabine until the maximum tolerated
      dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
      of 6 patients experience dose-limiting toxicity.

        -  Graft-versus-host disease (GVHD) prophylaxis: Patients who undergo bone marrow or
           peripheral blood stem cell transplantation receive tacrolimus IV continuously over 24
           hours or orally every 8-12 hours beginning on day -3 and methotrexate IV on days 1, 3,
           6, and 11. Patients who undergo UCB transplantation receive tacrolimus IV continuously
           over 24 hours or orally every 8-12 hours beginning on day -3 and mycophenolate mofetil
           (MMF) IV or orally 2 or 3 times daily on days -3 to 45 followed by a taper until day 100
           (unless there are signs of acute GVHD). Patients who undergo UCB transplantation without
           GVHD continue tacrolimus for 6 months followed by a taper and discontinued 1 year after
           transplantation.

        -  Allogeneic hematopoietic stem cell transplantation (HSCT) or allogeneic umbilical cord
           blood (UCB) transplantation: Patients undergo allogeneic HSCT (bone marrow or peripheral
           blood stem cells) or double UCB transplantation on day 0. Patients also receive
           filgrastim (G-CSF) IV or subcutaneously beginning on day 7 and continuing until blood
           counts recover.

        -  Maintenance therapy: Approximately 2 months after transplantation patients with ALL, M4
           or M5 AML, and those transplanted with AML in bone marrow relapse receive cytarabine
           intrathecally (IT) monthly for up to 5 doses. Patients with a history of CNS leukemia
           receive cytarabine IT once monthly during months 2-12 after HSCT.

      After completion of study therapy, patients are followed periodically for at least 4 years.

      PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.
    

Intervention name(s): filgrastim; clofarabine; melphalan; mycophenolate mofetil; tacrolimus; thiotepa; allogeneic bone marrow transplantation; allogeneic hematopoietic stem cell transplantation; peripheral blood stem cell transplantation
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Drug; Procedure; Procedure; Procedure
Intervention MeSH terms: Mycophenolic Acid; Melphalan; Thiotepa; Clofarabine; Tacrolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: graft versus host disease; adult acute lymphoblastic leukemia in remission; adult acute myeloid leukemia in remission; childhood acute lymphoblastic leukemia in remission; childhood chronic myelogenous leukemia; recurrent childhood acute myeloid leukemia; accelerated phase chronic myelogenous leukemia; acute undifferentiated leukemia; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; blastic phase chronic myelogenous leukemia; juvenile myelomonocytic leukemia; previously treated myelodysplastic syndromes; recurrent adult acute lymphoblastic leukemia; recurrent adult acute myeloid leukemia; relapsing chronic myelogenous leukemia; secondary acute myeloid leukemia; secondary myelodysplastic syndromes; childhood acute myeloid leukemia in remission; de novo myelodysplastic syndromes; recurrent childhood acute lymphoblastic leukemia; chronic phase chronic myelogenous leukemia; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); childhood myelodysplastic syndromes