Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission
Condition: B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Graft Versus Host Disease; L1 Childhood Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Graft vs Host Disease
Study type: Interventional
Phase: Phase 3

Summary: 
      This randomized phase III trial is studying tacrolimus, methotrexate, and sirolimus to see
      how well they work compared to tacrolimus and methotrexate in preventing graft-versus-host
      disease in young patients who are undergoing donor stem cell transplant for intermediate-risk
      or high-risk acute lymphoblastic leukemia in second complete remission and high risk acute
      lymphoblastic leukemia in first remission. Giving chemotherapy, such as thiotepa and
      cyclophosphamide, and total-body irradiation before a donor stem cell transplant helps stop
      the growth of cancer cells. It also helps stop the patient's immune system from rejecting the
      donor's stem cells. The donated stem cells may replace the patient's immune cells and help
      destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted
      cells from a donor can also make an immune response against the body's normal cells. Giving
      tacrolimus, methotrexate, and sirolimus after the transplant may stop this from happening. It
      is not yet known whether tacrolimus and methotrexate are more effective with or without
      sirolimus in preventing graft-versus-host disease.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. Compare the post-transplant 2-year event-free survival of pediatric patients with
      intermediate-risk or high-risk acute lymphoblastic leukemia (ALL) in second complete
      remission or high risk ALL in first remission undergoing allogeneic hematopoietic stem cell
      transplantation treated with graft-versus-host disease (GVHD) prophylaxis comprising
      tacrolimus and methotrexate with or without sirolimus.

      SECONDARY OBJECTIVES:

      I. Compare rates of relapses, transplant-related mortality, and acute and chronic GVHD in
      these patients.

      II. Evaluate the relative contribution of resistance by ALL blasts to cytolytic therapy
      (e.g., chemotherapy/irradiation) as a cause of relapse post-transplantation by correlating
      ALL in vivo blast resistance with in vivo sirolimus, inhibition levels of the mTOR pathway in
      patients treated with sirolimus, and altered resistance pathways in ALL blasts measured by
      microarray analysis.

      III. Evaluate the relative contribution of resistance by ALL blasts to the donor immune
      response as a cause of relapse post-transplantation by correlating the development of donor
      anti-ALL T-cell response, the development of acute and/or chronic GVHD, and the detection of
      altered ALL blast immunogenicity after transplant with increased minimal residual disease,
      persistent recipient chimerism, and relapse.

      OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified
      according to specific combinations of risk (intermediate CR2 vs high CR2 vs high CR1), donor
      type (matched sibling vs unrelated or other related), and stem cell source (filgrastim
      [G-CSF]-primed bone marrow vs unprimed bone marrow vs bone marrow vs peripheral blood vs
      umbilical cord blood).

      PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily on days -8 to -6 and
      receive thiotepa IV on days -5 and -4 and cyclophosphamide IV on days -3 and -2.

      ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: Patients undergo allogeneic hematopoietic
      stem cell transplantation on day 0.

      GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients are randomized to 1 of 2 treatment
      arms.

      ARM I: (experimental) Patients receive tacrolimus IV continuously or orally (when able) daily
      beginning on day -2 followed by a taper beginning on day 42 and continuing until day 98 (for
      patients undergoing matched sibling donor transplantation) OR tacrolimus IV continuously or
      orally daily beginning on day -2 followed by a taper beginning on day 100 and continuing
      until day 180 (for patients undergoing related, unrelated, or cord blood donor
      transplantation) in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3,
      and 6 (for patients with matched sibling and umbilical cord blood donors) OR days 1, 3, 6,
      and 11 (for patients with unrelated bone marrow and peripheral blood stem cell donors) and
      oral sirolimus daily beginning on day 0 followed by a taper beginning on day 180 and
      continuing until day 207.

      ARM II: (control) Patients receive tacrolimus and methotrexate as in arm I.

      After completion of study treatment, patients are followed periodically for approximately 5
      years.
    

Intervention name(s): thiotepa; cyclophosphamide; tacrolimus; methotrexate; sirolimus; total body irradiation
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Radiation
Intervention description(s): Given IV; Given IV; Given IV or orally; Given IV; Given orally; Part of the transplant preparatory regimen
Other intervention name(s): Oncotiotepa; STEPA; TESPA; Tespamin; TSPA; CPM; CTX; Cytoxan; Endoxan; Endoxana; FK 506; Prograf; amethopterin; Folex; methylaminopterin; Mexate; MTX; AY 22989; Rapamune; rapamycin; SLM; TBI
Intervention MeSH terms: Sirolimus; Cyclophosphamide; Thiotepa; Methotrexate; Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment