Clinical Trials /

Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

NCT01760655

Description:

This clinical trial studies reduced-intensity conditioning before donor stem cell transplant in treating patients with high-risk hematologic malignancies. Giving low-doses of chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It may also 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). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Hematopoietic and Lymphoid Malignancy
  • Hodgkin Lymphoma
  • Myelodysplastic Syndromes
  • Myeloma
  • Myeloproliferative Neoplasm
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies
  • Official Title: A Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 12D.501
  • SECONDARY ID: 2012-67
  • NCT ID: NCT01760655

Conditions

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Adult Acute Lymphoblastic Leukemia in Remission
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Blastic Phase Chronic Myelogenous Leukemia
  • Childhood Acute Lymphoblastic Leukemia in Remission
  • Childhood Burkitt Lymphoma
  • Childhood Chronic Myelogenous Leukemia
  • Childhood Diffuse Large Cell Lymphoma
  • Childhood Immunoblastic Large Cell Lymphoma
  • Childhood Myelodysplastic Syndromes
  • Childhood Nasal Type Extranodal NK/T-cell Lymphoma
  • Chronic Myelomonocytic Leukemia
  • Chronic Phase Chronic Myelogenous Leukemia
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • de Novo Myelodysplastic Syndromes
  • Essential Thrombocythemia
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Hepatosplenic T-cell Lymphoma
  • Intraocular Lymphoma
  • Juvenile Myelomonocytic Leukemia
  • Nodal Marginal Zone B-cell Lymphoma
  • Noncutaneous Extranodal Lymphoma
  • Peripheral T-cell Lymphoma
  • Polycythemia Vera
  • Post-transplant Lymphoproliferative Disorder
  • Previously Treated Myelodysplastic Syndromes
  • Primary Myelofibrosis
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Childhood Acute Myeloid Leukemia
  • Recurrent Childhood Anaplastic Large Cell Lymphoma
  • Recurrent Childhood Grade III Lymphomatoid Granulomatosis
  • Recurrent Childhood Large Cell Lymphoma
  • Recurrent Childhood Lymphoblastic Lymphoma
  • Recurrent Childhood Small Noncleaved Cell Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Recurrent/Refractory Childhood Hodgkin Lymphoma
  • Refractory Anemia With Excess Blasts
  • Refractory Anemia With Excess Blasts in Transformation
  • Refractory Cytopenia With Multilineage Dysplasia
  • Refractory Hairy Cell Leukemia
  • Refractory Multiple Myeloma
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • T-cell Large Granular Lymphocyte Leukemia
  • Testicular Lymphoma
  • Waldenström Macroglobulinemia

Interventions

DrugSynonymsArms
Fludarabine phosphateFludarabine, FludaraTreatment (RIC and stem cell transplant)
ThiotepaN,N'N'-triethylenethiophosphoramide, 1,1',1''-phosphorothioyltriaziridineTreatment (RIC and stem cell transplant)
Therapeutic allogeneic lymphocytesAllogeneic Lymphocytes, ALLOLYMPHTreatment (RIC and stem cell transplant)
CyclophosphamideEndoxan, Cytoxan, Neosar, Procytox, Revimmune, (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide, LyophilizedcytoxanTreatment (RIC and stem cell transplant)
TacrolimusFK-506, fujimycin, Prograf, Advagraf, ProtopicTreatment (RIC and stem cell transplant)
Mycophenolate mofetilMMF, CellCept, MyforticTreatment (RIC and stem cell transplant)

Purpose

This clinical trial studies reduced-intensity conditioning before donor stem cell transplant in treating patients with high-risk hematologic malignancies. Giving low-doses of chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It may also 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). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect.

Detailed Description

      PRIMARY OBJECTIVE:

      1. To compare the rate of disease-free survival (DFS) at 1 year post hematopoietic stem cell
      transplant (HSCT) in patients undergoing HSCT treated on this successor Thomas Jefferson
      University (TJU) 2 Step reduced intensity conditioning (RIC) haploidentical regimen and
      compare it with that of the initial 2 Step RIC regimen.

      SECONDARY OBJECTIVES:

        1. To assess the 100 day regimen-related mortality (RRM) in patients undergoing HSCT on
           this treatment protocol.

        2. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients
           undergoing treatment on this regimen.

        3. To evaluate engraftment rates and lymphoid reconstitution in patients treated on this
           trial.

        4. To assess overall survival at 1 and 3 years past HSCT in patients treated on this trial.

      OUTLINE:

      REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV)
      over 60 minutes on days -15 to -12, thiotepa IV over 2 hours on days -15 to -13, donor
      lymphocyte infusion (DLI) on day -6, and cyclophosphamide IV over 2 hours on days -3 and -2.
      Patients also undergo total-body irradiation (TBI) on day -10.

      TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day
      0.

      GVHD PROPHYLAXIS: Patients receive tacrolimus IV on days -1 to 42 followed by taper and
      mycophenolate mofetil IV twice daily (BID) on days -1 to 28.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (RIC and stem cell transplant)ExperimentalREDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 60 minutes on days -15 to -12, thiotepa IV over 2 hours on days -15 to -13, donor lymphocyte infusion (DLI) on day -6, and cyclophosphamide IV over 2 hours on days -3 and -2. Patients also undergo TBI on day -10. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV on days -1 to 42 followed by taper and mycophenolate mofetil IV BID on days -1 to 28.
  • Fludarabine phosphate
  • Thiotepa
  • Cyclophosphamide
  • Tacrolimus
  • Mycophenolate mofetil

Eligibility Criteria

        Inclusion Criteria:

          1. Any patient with a high-risk hematologic or oncologic diagnosis in which allogeneic
             HSCT is thought to be beneficial, and in whom front-line therapy has already been
             applied. High risk is defined as:

               1. Acute myeloid leukemia with high risk features as defined by:

                    -  Age greater than or equal to 60

                    -  Secondary AML (prior therapy or hematologic malignancy)

                    -  Normal cytogenetics but FLT3/ITD positive

                    -  Any relapse or primary refractory disease

                    -  Greater than 3 cytogenetic abnormalities or any one of the following
                       cytogenetic abnormalities: -5/del(5q), -7/del(7q),
                       Abn(9q),(11q),(3q),(21q),(17p),t(6;9), t(6;11), t(11;19),
                       +8,del(12p),inv(3),t(10;11),-17, 11q 23

                    -  Any single autosomal monosomy

               2. Acute lymphoid leukemia in 1st or 2nd morphological remission. ALL with any
                  morphological evidence of disease will not be eligible.

               3. Myelodysplasia (MDS) other than refractory anemia (RA), refractory anemia with
                  rare sideroblasts (RARS), or isolated 5q- syndrome subtypes.

               4. Hodgkin's or Non-Hodgkin's lymphoma in 2nd or greater remission or with
                  persistent disease.

               5. Myeloma with evidence of persistent disease after front-line therapy.

               6. Chronic myeloid leukemia (CML) resistant to signal transducer inhibitor (STI)
                  therapy

               7. Myelofibrosis and CMML

               8. Essential Thrombocytopenia or Polycythemia Vera with current or past evidence of
                  evolution to acute leukemia

               9. Any hematological malignancy not cited above which is thought to be high-risk
                  with increased chance of post HSCT relapse. Patients in this category require
                  specific approval of the PI and the TJU BMT attending physician group for
                  entrance.

              10. Any hematological malignancy or dyscrasia not cited above which is thought to be
                  high-risk with increased chance of post HSCT relapse.

              11. Any patient who has an aggressive disease that would normally be treated on a
                  myeloablative study, but is prevented from doing so by factors in their past
                  medical history. Examples are patients with previous treatment with radiation
                  therapy precluding TBI, or a past history of myeloablative therapy, precluding a
                  2nd myeloablative regimen.

              12. Patients with aplastic anemia may be treated on this protocol, with outcomes
                  reported descriptively.

          2. Patients must have a related donor who is at least a 4 antigen match at the Human
             Leukocyte Antigen (HLA)-A; B; C; DR loci. Patients with only a 1 out of 8 mismatch in
             the GVH direction will be classified in the matched related category

          3. Patients must adequate organ function:

               1. Left ventricular end diastolic function (LVEF) of >50%

               2. Diffusion Lung Capacity of Oxygen (DLCO) >50% of predicted corrected for
                  hemoglobin

               3. Adequate liver function as defined by a serum bilirubin <1.8, aspartate
                  aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5X upper limit of
                  normal

               4. Creatinine Clearance of ≥ 60 mL/min 4) Patients must have adequate KPS and HCT-CI
                  scores:

               1. Patients < age 60 years must have a KPS of ≥80% and an HCT-CI score of 5 or less

               2. Patients aged 60 to 65 years must have a KPS of ≥80% and an HCT-CI score of 4 or
                  less

               3. Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or
                  less

               4. Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or
                  less 5) Patients must be willing to use contraception if they have childbearing
                  potential 6) Patient or patient's guardian is able to give informed consent

        Exclusion Criteria:

          1. HIV positive

          2. Active involvement of the central nervous system with malignancy

          3. Pregnancy

          4. Patients with life expectancy of < 6 months for reasons other than their underlying
             hematologic/oncologic disorder

          5. Patients who have received alemtuzumab or ATG within 8 weeks of the transplant
             admission.

          6. Patients with evidence of another malignancy, exclusive of a skin cancer that requires
             only local treatment, should not be enrolled on this protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease-free survival (DFS)
Time Frame:1 year
Safety Issue:
Description:The primary null hypothesis is that 1 year DFS rate is at most 35%. 35% is the rounded number (actual 36%) representing the DFS at 1 year of patients treated on the initial TJU 2 Step RIC HSCT trial and consistent with the outcome of patients treated on similar protocols outside of our institution.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:1 year and 3 years
Safety Issue:
Description:
Measure:Incidence of Regimen Related Toxicity
Time Frame:Up to 1 year
Safety Issue:
Description:Graded according to the National Cancer Institute (NCI) Common Toxicity Criteria version 4.0
Measure:Immune reconstitution
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Incidence and degree of GVHD
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Engraftment rates
Time Frame:Up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Cancer Center at Thomas Jefferson University

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