Clinical Trials /

Laboratory-Treated Lymphocyte Infusion After Haploidentical Donor Stem Cell Transplant

NCT00376480

Description:

RATIONALE: Giving total-body irradiation and chemotherapy, such as thiotepa and fludarabine, 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 make an immune response against the body's normal cells. Giving methylprednisolone and antithymocyte globulin before transplant and peripheral blood cells that have been treated in the laboratory after transplant may stop this from happening. PURPOSE: This phase I trial is studying the side effects and best dose of laboratory-treated peripheral blood cell infusion after donor stem cell transplant in treating patients with hematologic cancers or other diseases.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Refractory Anemia
  • Refractory Anemia with Excess Blasts
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Laboratory-Treated Peripheral Blood Cell Infusion After Donor Stem Cell Transplant in Treating Patients With Hematologic Cancers or Other Diseases
  • Official Title: Delayed Infusion of Ex Vivo Anergized Peripheral Blood Mononuclear Cells Following CD34 Selected Peripheral Blood Stem Cell Transplantation From a Haploidentical Donor for Patients With Acute Leukemia and Myelodysplasia

Clinical Trial IDs

  • ORG STUDY ID: CDR0000491633
  • SECONDARY ID: DFCI-05030
  • SECONDARY ID: MDA-2005-0695
  • NCT ID: NCT00376480

Conditions

  • Leukemia
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
anti-thymocyte globulin
peripheral blood lymphocyte therapy
fludarabine phosphate
methylprednisolone
thiotepa

Purpose

RATIONALE: Giving total-body irradiation and chemotherapy, such as thiotepa and fludarabine, 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 make an immune response against the body's normal cells. Giving methylprednisolone and antithymocyte globulin before transplant and peripheral blood cells that have been treated in the laboratory after transplant may stop this from happening. PURPOSE: This phase I trial is studying the side effects and best dose of laboratory-treated peripheral blood cell infusion after donor stem cell transplant in treating patients with hematologic cancers or other diseases.

Detailed Description

      OBJECTIVES:

      Primary

        -  Establish the feasibility of delayed infusion of ex vivo anergized donor peripheral
           blood mononuclear cells (PBMC) after CD34-selected megadose haploidentical hematopoietic
           stem cell transplantation (HSCT) in patients with hematopoietic cancers or other
           diseases.

        -  Determine the feasibility of collecting parental allogeneic stimulator cells to induce
           anergy to the nonshared donor-recipient haplotype in these patients.

        -  Determine the feasibility of collecting donor PBMC as a source of T cells for ex vivo
           anergization.

        -  Determine the number of transplanted individuals who meet the criteria for proceeding to
           delayed infusion of ex vivo anergized donor PBMC.

        -  Establish the safety of delayed infusion of ex vivo anergized donor PBMC by establishing
           the maximum number of donor T cells that can be infused without unacceptable
           graft-versus-host disease.

      Secondary

        -  Evaluate, in vitro, the induction and specificity of alloantigen hyporesponsiveness in
           donor PBMC after ex vivo anergization.

        -  Assess, in vitro, the function of immune cells engrafted in these patients.

        -  Assess, in vitro, whether alloantigen hyporesponsive donor T cells are present in these
           patients.

        -  Develop, preliminarily, in vitro data on the extent of pathogen-specific immunity and
           its rate of recovery.

        -  Describe the patterns of opportunistic infections in these patients.

      OUTLINE: This is a multicenter, dose-escalation study of ex vivo anergized allogeneic
      peripheral blood mononuclear cells (PBMC). Patients who are treated on any dose level except
      dose level 1 are stratified according to age (under 17 [pediatric] vs 17 and over [adult]).

        -  Myeloablative conditioning regimen: Patients undergo total-body irradiation twice daily
           on days -11 to -9. Patients also receive thiotepa IV over 4 hours on days -8 and -7,
           fludarabine phosphate IV over 30 minutes on days -7 to -3, and anti-thymocyte globulin
           IV over 8 hours and methylprednisolone IV over 15-30 minutes on days -6 to -3.

        -  Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo
           CD34-selected PBSCT on day 0.

        -  Ex vivo anergized allogeneic PBMC infusion: If cells have engrafted and patients are
           free of active uncontrolled infection and graft-vs-host disease, patients undergo
           allogeneic or autologous PBMC infusion on day 35 or 42.

      Cohorts of 3-8 patients receive escalating doses of ex vivo anergized allogeneic PBMCs until
      the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of
      5 or 3 of 8 patients experience dose-limiting toxicity.

      After completion of study, patients are followed periodically for 2 years.

      PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
    

Trial Arms

NameTypeDescriptionInterventions

Eligibility Criteria

        DISEASE CHARACTERISTICS:

          -  Diagnosis of 1 of the following:

               -  Acute lymphocytic leukemia

                    -  In ≥ second complete remission (CR), defined as < 5% blasts in bone marrow
                       (BM) and no active extramedullary disease OR in first CR with any of the
                       following high risk features:

                         -  History of induction failure

                         -  Philadelphia chromosome positive

                         -  t(4;11) by cytogenetic analysis

                         -  Any infant with MLL rearrangements on cytogenetic analysis

                    -  No relapse with isolated extramedullary disease after completion of prior
                       treatment

               -  Acute myeloid leukemia

                    -  Failed induction therapy after < 3 courses

                    -  In ≥ second CR, defined as < 5% blasts in BM and no active extramedullary
                       disease OR in first CR with any of the following high-risk features:

                         -  History of induction failure = 5q- or monosomy 7 cytogenetic findings

               -  Any of the following myelodysplastic syndromes:

                    -  Refractory anemia (RA) with excess blasts (RAEB) with a high International
                       Prognostic Scoring System (IPSS) score or score of intermediate-1(INT-1) or
                       intermediate-2 (INT-2)

                    -  RAEB in transformation with INT-1, INT-2, or high IPSS score

                    -  RA with INT-2 score

          -  Patients must have a healthy, related donor who is at least genotypically HLA-A, B, C,
             and DR haploidentical to the patient

               -  No suitably matched family donor defined by genotypic or phenotypic identity for
                  ≥ 5/6 A, B, or DR loci

               -  No immediately available genotypically matched (6/6) unrelated marrow donor

               -  No immediately available umbilical cord blood donor with suitable cell dose after
                  a search ≥ 2 months

               -  Patients whose medical condition is at high risk of deteriorating or whose
                  disease is at high risk of progression during a donor search are eligible

          -  Has a parent with a haplotype that is disparate from that of the donor for the
             haplotype shared by the patient and parent, but not shared by the patient and donor OR
             patient is able to donate sufficient autologous cells by peripheral blood draw or
             unstimulated leukapheresis

          -  No active CNS disease

        PATIENT CHARACTERISTICS:

          -  Room air O_2 saturation > 95% unless the lungs are involved with disease

          -  No clinical evidence of pulmonary insufficiency unless the lungs are involved with
             disease

          -  AST and ALT < 3 times upper limit of normal (ULN)*

          -  Bilirubin < 2.0 mg/dL*

          -  Creatinine < 2 times ULN OR creatinine clearance or glomerular filtration rate > 50%
             of the lower limit of normal

          -  LVEF > 45% OR shortening fraction > 20%

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception

          -  No active infection, defined as absence of an infectious diagnosis or (in patients who
             have had a recent positive infectious diagnosis) the resolution of fever,
             documentation of negative cultures or antigen testing, continuation or completion of a
             course of appropriate therapy, and presence of stable to resolving clinical symptoms

          -  No evidence of HIV infection OR known HIV positivity NOTE: *Does not apply if liver is
             involved with disease

        PRIOR CONCURRENT THERAPY:

          -  See Disease Characteristics

          -  No prior stem cell transplantation

          -  No other concurrent immunosuppressive therapy
      
Maximum Eligible Age:50 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Feasibility
Time Frame:
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Hyporesponsiveness by donor T cells
Time Frame:
Safety Issue:
Description:
Measure:Immune cell function
Time Frame:
Safety Issue:
Description:
Measure:Pathogen-specific immunity
Time Frame:
Safety Issue:
Description:
Measure:Rate of recovery
Time Frame:
Safety Issue:
Description:
Measure:Opportunistic infection patterns
Time Frame:
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Unknown status
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • refractory anemia with excess blasts in transformation
  • adult acute lymphoblastic leukemia in remission
  • refractory anemia with excess blasts
  • refractory anemia
  • adult acute myeloid leukemia in remission
  • childhood acute lymphoblastic leukemia in remission
  • childhood acute myeloid leukemia in remission
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • secondary acute myeloid leukemia
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • 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)
  • secondary myelodysplastic syndromes
  • childhood myelodysplastic syndromes

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