Clinical Trials /

Reduced Intensity Chemotherapy and Radiation Therapy Before Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies

NCT02566304

Description:

This clinical trial studies the use of reduced intensity chemotherapy and radiation therapy before donor stem cell transplant in treating patients with hematologic malignancies. Giving low doses of chemotherapy, such as cyclophosphamide and fludarabine phosphate, before a donor stem cell transplant may help 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). Reducing the intensity of the chemotherapy and radiation may also reduce the side effects of the donor stem cell transplant.

Related Conditions:
  • Acute Myeloid Leukemia
  • Aplastic Anemia
  • Chronic Myelomonocytic Leukemia
  • Hematopoietic and Lymphoid Malignancy
  • Hodgkin Lymphoma
  • Myelodysplastic Syndrome with Isolated del(5q)
  • Myelodysplastic Syndromes
  • Myeloma
  • Myeloproliferative Neoplasm
  • Non-Hodgkin Lymphoma
  • Refractory Anemia
  • Refractory Anemia with Excess Blasts-1
  • Refractory Anemia with Excess Blasts-2
  • Refractory Cytopenia with Multilineage Dysplasia
  • Refractory Cytopenia with Multilineage Dysplasia and Ring Sideroblasts
  • Refractory anemia with ring sideroblasts
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Reduced Intensity Chemotherapy and Radiation Therapy Before Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies
  • Official Title: A Two Step Approach to Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 15D.323
  • SECONDARY ID: 2015-054
  • SECONDARY ID: NCI-2015-01506
  • NCT ID: NCT02566304

Conditions

  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia in Remission
  • Aplastic Anemia
  • Chronic Myelomonocytic Leukemia
  • Hodgkin Lymphoma
  • Indolent Non-Hodgkin Lymphoma
  • Malignant Neoplasm
  • Myelodysplastic Syndrome
  • Myeloproliferative Neoplasm
  • Plasma Cell Myeloma
  • Refractory Anemia
  • Refractory Anemia With Excess Blasts
  • Refractory Anemia With Ring Sideroblasts
  • Refractory Cytopenia With Multilineage Dysplasia
  • Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

Interventions

DrugSynonymsArms
FludarabineFludarabine phosphate, FludaraRIC HSCT, GVHD prophylaxis
T Cell-Depleted Donor Lymphocyte InfusionRIC HSCT, GVHD prophylaxis
CyclophosphamideEndoxan, Cytoxan, Neosar, Procytox, Revimmune, Cycloblastin, Cytophosphane, CPRIC HSCT, GVHD prophylaxis
TacrolimusFK-506, Fujimycin, Prograf, Advograf, ProtopicRIC HSCT, GVHD prophylaxis
Mycophenolate mofetilMycophenolic acid, MMF, CellCept, MyforticRIC HSCT, GVHD prophylaxis

Purpose

This clinical trial studies the use of reduced intensity chemotherapy and radiation therapy before donor stem cell transplant in treating patients with hematologic malignancies. Giving low doses of chemotherapy, such as cyclophosphamide and fludarabine phosphate, before a donor stem cell transplant may help 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). Reducing the intensity of the chemotherapy and radiation may also reduce the side effects of the donor stem cell transplant.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To demonstrate efficacy of this approach over the historical 2 step reduced intensity
      conditioning (RIC) approaches in the "vulnerable" population defined as: patients with
      hematopoietic cell transplant (HCT)-co-morbidity index (CI)/age scores >= 2, but no more than
      a score of 5 as based on the Sorror et al. data.

      SECONDARY OBJECTIVES:

      I. To compare the non-relapse mortality (NRM) and relapse related mortality (RRM) rates at 1
      year for patients treated on this study to the that of patients undergoing haploidentical RIC
      hematopoietic stem cell transplantation (HSCT) as reported in the literature and as observed
      in the 2 step RIC trials.

      II. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients
      undergoing treated on the Thomas Jefferson University (TJU) RIC 2 step approach.

      III. To evaluate engraftment rates and lymphoid reconstitution in patients treated on the TJU
      RIC 2 step approach.

      OUTLINE:

      RIC: Patients receive fludarabine phosphate intravenously (IV) over 60 minutes on days -10 to
      -8 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients also undergo total body
      irradiation (TBI) followed by a donor lymphocyte infusion (DLI) on day -6.

      TRANSPLANT: Patients undergo cluster of differentiation (CD)34+ peripheral blood stem cell
      transplant on day 0.

      GVHD PROPHYLAXIS: Patients receive tacrolimus orally (PO) beginning day -1 with a taper
      initiated on day 42 and mycophenolate mofetil IV twice daily (BID) on days -1 to 28 in the
      absence of GVHD.

      After completion of study treatment, patients are followed up for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
RIC HSCT, GVHD prophylaxisExperimentalRIC: Patients receive fludarabine phosphate IV over 60 minutes on days -10 to -8 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients also undergo TBI followed by a DLI on day -6. TRANSPLANT: Patients undergo CD34+ peripheral blood stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus PO beginning day -1 with a taper initiated on day 42 and mycophenolate mofetil IV BID on days -1 to 28 in the absence of GVHD.
  • Fludarabine
  • Cyclophosphamide
  • Tacrolimus
  • Mycophenolate mofetil

Eligibility Criteria

        Inclusion Criteria:

          1. Patients treated on this study will have:

               1. Acute myeloid leukemia in morphologic CR not requiring treatment for their
                  disease for 6 weeks

               2. A history of AML with < 20% residual blasts after induction therapy and
                  persisting with <20% blasts for at least 8 weeks without reinduction.

               3. RA or RARS or isolated 5q- can proceed to transplant without any treatment

               4. RAEB-1, RCMD+/-RS, or MDS NOS with stable disease for 6 months (as documented by
                  serial bone marrow examinations) in the absence of any therapy but growth factors
                  or transfusion support. Patients who require treatment to "control their disease"
                  must show chemo-responsiveness

               5. CMML or RAEB-2 must demonstrate chemo-responsiveness. Chemo-responsiveness is
                  defined as a blast percentage decrease by at least 5 percentage points and there
                  must be less than 20% blasts after treatment and at the time of transplant

               6. Hodgkin or Indolent Non-Hodgkin's lymphoma

               7. Myeloma with < 5% plasma cells in the marrow

               8. Myeloproliferative disorders

               9. Aplastic Anemia

              10. A hematological or oncological disease (not listed) in which allogeneic HSCT is
                  thought to be beneficial, and the disease is chemoresponsive.

              11. Patients without clear manifestation of their disease status in terms of stage
                  and/or responsiveness should be discussed with the PI and enrollment analysis
                  should be documented in the study records.

          2. Patients must have a related donor who is HLA mismatched at 2, 3, or 4 antigens at the
             HLA-A; B; C; DR loci in the GVHD direction. (Patients with related donors who are HLA
             identical or are a 1-antigen mismatch may be treated on this therapeutic approach, but
             will have their outcomes will not be part of the statistical aims of the study (see
             Statistical Section). The HLA matched related category includes patients with a
             syngeneic donor.

          3. Patients must have had front line therapy for their disease.

          4. Patients must adequate organ function:

               1. LVEF (Left ventricular end diastolic function) of >45%. LVEF between 45% and 54%
                  must have negative stress test with increase in EF of 3-5 points with stress

               2. DLCO (Diffusing Capacity of the Lung for Carbon Monoxide ) ≥45% of predicted
                  corrected for hemoglobin, FEV-1 (forced expiratory volume at 1 second ≥50% of
                  predicted

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

               4. Creatinine Clearance of ≥ 60 mL/min

          5. HCT-CI/Age Score ≤ 5 points (Patients with greater than 5 points will be allowed for
             trial with approval of the PI and the Co-PI or his designee. This is an adjustment to
             account for healthy patients who meet the spirit of this protocol but have histories
             that result in higher than HCT-CI 5 points. An example is a patient with a solid tumor
             malignancy in their remote history (adds 3 points to HCT-CI total) where the treatment
             for the malignancy occurred years to decades before and there has been complete
             recovery of toxicities.

          6. KPS≥ 90% patients older than 70 years, KPS≥ 80% patients younger than 70 years

          7. Patients must be willing to use contraception if they have childbearing potential

        Exclusion Criteria:

          1. Performance status < 90% in patients 70 years old or greater, <80% in patients less
             than age 70 years

          2. HCT-CI/age Score >5 points (Patients with greater than 5 points will be allowed for
             trial with approval of the Principal Investigator and the Co-Principal Investigator or
             his designee. This is an adjustment to account for healthy patients who meet the
             spirit of this protocol but have histories that result in higher than HCT-CI 5 points.
             An example is a patient with a solid tumor malignancy in their remote history (adds 3
             points to HCT-CI total) where the treatment for the malignancy occurred years to
             decades before and there has been complete recovery of toxicities.

          3. A diagnosis of CMML, unless in morphologic CR

          4. HIV positive

          5. Active involvement of the central nervous system with malignancy

          6. Inability to obtain informed consent from patient or surrogate

          7. Pregnancy

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

          9. Patients who have received alemtuzumab or antithymocyte globulin within 8 weeks of the
             transplant admission. The absence of these therapies in the medical record will serve
             as documentation that they were not given.

         10. 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:Overall Survival (OS)
Time Frame:At 1 year post HSCT
Safety Issue:
Description:OS will be estimated using Kaplan-Meier curves. The 1-year OS rate and corresponding 95% confidence interval will be estimated from the Kaplan-Meier curve for the OS.

Secondary Outcome Measures

Measure:Relapse Related Mortality (RRM)
Time Frame:At 1 year post HSCT
Safety Issue:
Description:Will be reported descriptively. RRM may also be estimated using Kaplan Meier curves and/or cumulative incidence analyses.
Measure:Non-Relapse Mortality (NRM)
Time Frame:At 1 year post HSCT
Safety Issue:
Description:Will be reported descriptively. NRM may also be estimated using Kaplan Meier curves and/or cumulative incidence analyses.
Measure:Incidence and severity of GVHD
Time Frame:Up to 1 year post HSCT
Safety Issue:
Description:Will be reported descriptively
Measure:Engraftment rates
Time Frame:Up to 1 year post HSCT
Safety Issue:
Description:Will be reported descriptively
Measure:Lymphoid reconstitution
Time Frame:Up to 1 year post HSCT
Safety Issue:
Description:Lymphoid reconstitution will be evaluated monthly to every other month during the first year post HSCT and will be reported descriptively.

Details

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

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