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Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Cancer

This study has been terminated.
(terminated early due to meeting end point with fewer patients than anticipated)
Sponsor:
Collaborator:
Blood and Marrow Transplant Group of Georgia
Information provided by (Responsible Party):
Northside Hospital, Inc.
ClinicalTrials.gov Identifier:
NCT00818961
First received: January 7, 2009
Last updated: October 28, 2013
Last verified: October 2013

January 7, 2009
October 28, 2013
May 2005
March 2011   (final data collection date for primary outcome measure)
Survival at Day 100 [ Time Frame: 100 day ] [ Designated as safety issue: No ]
Survival at Day 100
Survival at day 100 [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00818961 on ClinicalTrials.gov Archive Site
  • Overall Survival at 1 Year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Evaluation of overall survival at 1 year (# of patients who are alive at 1 year post-transplant)
  • Non-relapse Mortality at Day 100 [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    patients are evaluable for their cause of death at Day 100
  • Non-relapse Mortality at 1 Year Post-transplant [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    Number of patients who died of non-relapse causes at one year. this is in clusive of all patients who were transplanted on study even though only 10 patients died at by 1 year time point. This outcome will be referenced in the donor chimerism outcome. Only 26/36 patients were eligible for this time point as that is all that were alive.
  • Complete Donor Chimerism [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Complete donor chimerism (defined as >/= 95% donor cells in peripheral blood CD3+ and CD33+ was measured.
  • Neutrophil Recovery [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    The number of patients experiencing neutrophil recovery post transplant
  • Platelet Engraftment [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    The number of patients experiencing platelet engraftment post-transplant
  • Number of Patients Requiring the Use of Donor Leukocyte Infusion (DLI) for Early Mixed T-cell Chimerism [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    DLI is used for patients with mixed chimerism following transplant
  • Number of Patients Experiencing Grade 2-4 Acute Graft-versus-host Disease Post-transplant [ Time Frame: patients were followed for 2 years ] [ Designated as safety issue: Yes ]
    patients experiencing acute graft versus host disease post-transplant
  • Number of Patients Experiencing Chronic Graft Versus Host Disease [ Time Frame: >100 days post-transplant ] [ Designated as safety issue: Yes ]
  • Number of Patients Experiencing Veno-occlusive Disease (VOD) Post-transplant [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
    Patients will be evaluated up to 4 years post transplant
  • CD34+ and CD3+ cell dose [ Designated as safety issue: No ]
  • Degrees of donor-recipient lymphoid and myeloid chimerism in peripheral blood [ Designated as safety issue: No ]
  • Neutrophil, platelet, and red cell recovery [ Designated as safety issue: No ]
  • Effect of donor lymphocyte infusions on donor-host lymphoid and myeloid chimerism [ Designated as safety issue: No ]
  • Incidence and severity of acute and chronic graft-versus-host disease [ Designated as safety issue: No ]
  • Non-hematologic effects attributable to the preparative regimen [ Designated as safety issue: No ]
  • Incidence of veno-occlusive disease [ Designated as safety issue: No ]
  • Relapse of malignancy or disease control [ Designated as safety issue: No ]
  • Transplant-related mortality at day 100 and 1 year [ Designated as safety issue: No ]
  • Disease-free survival and overall survival [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Cancer
Reduced Intensity Allogeneic Stem Cell Transplantation With Matched Unrelated Donors for Patients With Hematologic Malignancies

RATIONALE: Giving low doses of chemotherapy 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). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving a monoclonal antibody, such as alemtuzumab, before transplant and tacrolimus and methotrexate after transplant may stop this from happening.

PURPOSE: This phase II trial is studying the side effects of donor stem cell transplant and to see how well it works in treating patients with high-risk hematologic cancer.

OBJECTIVES:

  • To evaluate the safety and toxicity of a reduced-intensity conditioning regimen followed by allogeneic bone marrow or peripheral blood stem cell transplantation from an HLA-matched unrelated donor in patients with high-risk hematologic malignancies.
  • To evaluate engraftment by peripheral blood chimerism analysis.
  • To determine the incidence and severity of acute and chronic graft-versus-host disease following the transplant.
  • To examine the possibility of controlling hematologic malignancies by induction of a graft-versus-leukemia/tumor effect.
  • To determine the disease-free survival, relapse, transplant-related mortality, and death from all causes.

OUTLINE:

  • Reduced-intensity conditioning regimen: Patients receive 1 of 2 conditioning regimens according to diagnosis.

    • Regimen 1 (acute leukemia, myelodysplastic syndromes, myeloproliferative syndrome, or chronic myelogenous leukemia): Patients receive fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -6 to -3 or orally 4 times daily on days -7 to -3.
    • Regimen 2 (lymphoproliferative malignancies): Patients receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 1 hour on days -5 to -3. Patients with CD20+ malignancies also receive rituximab IV over 4-6 hours on days -13, -6, 1, and 8.
  • Transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0.
  • Graft-versus-host disease (GVHD) prophylaxis: Patients receive low-dose alemtuzumab subcutaneously on days -11 to -9 and tacrolimus IV over 24 hours beginning on day -3 and then orally twice daily beginning on day 14 and continuing until day 60, followed by a taper until day 180 in the absence of clinically significant GVHD. Patients also receive methotrexate on days 1, 3, and 6.

Patients who exhibit persistent mixed chimerism or disease relapse/progression despite full withdrawal of immunosuppression may receive up to 3 donor lymphocyte infusions.

Blood samples are taken on days 30, 60, and 100 and then every 4 weeks thereafter for chimerism studies by PCR analysis.

After completion of study therapy, patients are followed periodically for up to 60 months.

Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Diseases
  • Biological: alemtuzumab
    43 mg subcutaneously over 3 days (3 mg on day -11, 10 mg on day -10, 30 mg on day -9)
    Other Name: Campath
  • Biological: graft-versus-tumor induction therapy
    curative potential of allogeneic transplant results from the immune anti-tumor effect of donor cells or GVT/GVL
  • Biological: rituximab
    in patients with Cd20+ malignancies: rituximab 375 mg/m*2 day -13. rituximab 1000 mg/m*2 on days, -6, +1, +8.
    Other Name: Rituxan
  • Drug: busulfan
    For patients with AML, CML, MDS, MPS and ALL only: IV or oral busulfan may be given IV busulfan: 130 mg/m2 over 3 hours once daily on days -6, -5, -4 and -3 Oral busulfan: taken every 6 hours x 15 doses beginning on day -7 at 6pm and continuing through day -3 at 6am. 1 mg/kg test dose will be given prior to day -7 and PK samples will be drawn to calculate AUC.
  • Drug: cyclophosphamide
    750 mg/m2 infused over 1 hour once daily on days -5, -4 and -3. Cyclophosphamide will be started approximately 4 hours after the start of Fludarabine
    Other Name: Cytoxan
  • Drug: fludarabine phosphate
    For patients with CLL, NHL & HD: 30 mg/m2 infused over 30 minutes once daily on days -5, -4 and -3 For patients with AML, CML, MDS, MPS and ALL: 40 mg/m2 infused over 30 minutes once daily on days -6, -5, -4 and -3.
    Other Name: Fludara
  • Drug: methotrexate
    5 mg/m2 administered on days +1, +3 and +6
  • Drug: tacrolimus
    0.03mg/kg/day infused over 24 hours starting on day -1 and switched to oral (twice daily divided dose) on day 14 or when able to tolerate PO
    Other Name: Prograf; FK506
  • Procedure: allogeneic bone marrow transplantation
    Recipients will receive an allogeneic transplant on day 0 after receiving high-dose chemotherapy. This trial uses matched unrelated donor stem cells.
    Other Name: HSCT, allo transplant
Hematopoietic Stem Cell Transplantation
All patients receive a hematopoietic stem cell transplant using one of two chemotherapy regimens based on donor type
Interventions:
  • Biological: alemtuzumab
  • Biological: graft-versus-tumor induction therapy
  • Biological: rituximab
  • Drug: busulfan
  • Drug: cyclophosphamide
  • Drug: fludarabine phosphate
  • Drug: methotrexate
  • Drug: tacrolimus
  • Procedure: allogeneic bone marrow transplantation

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
36
March 2012
March 2011   (final data collection date for primary outcome measure)
  • Diagnosis of one of the following hematological malignancies:

    • CML, with 1 of the following:

      • In first CP AND failed imatinib mesylate therapy, defined as failure to obtain a hematologic remission at 3 months or a major cytogenetic response (i.e., Ph+ cells < 35%) at 6 months or demonstrated clonal evolution or disease progression during therapy
      • In accelerated phase with < 15% blasts
      • In blast crisis that has entered into a second CP following induction chemotherapy
    • AML, with 1 of the following:

      • In second or subsequent complete remission (CR) (i.e., < 5% blasts by morphology, no residual leukemia by flow cytometry, and absence of cytogenetic abnormalities)
      • Failed primary induction chemotherapy, but subsequently entered into a CR with ≤ 2 subsequent re-induction chemotherapy treatment(s)
      • In first CR with intermediate-risk or poor-risk cytogenetics
    • ALL with 1 of the following:

      • In second or subsequent CR
      • In first CR AND presence of t(9;22)
    • MDS, with the following:

      • High-risk disease, defined by IPSS score of ≥ 1.5 at diagnosis AND meets 1 of the following criteria:

        • ≤ 10% blasts at diagnosis
        • In morphologic CR (< 5% blasts) following cytoreductive chemotherapy
    • CMML, with 1 of the following:

      • ≤ 10% blasts at diagnosis
      • In morphologic CR (< 5% blasts) following cytoreductive chemotherapy
    • CLL/PLL with the following:

      • Rai stage I-IV disease
      • Failed ≥ 1 prior chemotherapy regimen (including fludarabine phosphate) or ASCT
      • Documented chemosensitive or stable, non-bulky disease prior to transplant, defined as < 20% bone marrow involvement AND lymph node size < 3 cm in axial diameter
      • No bulky tumor masses, elevated lactate dehydrogenase (LDH), B symptoms, or progressive disease prior to transplant
    • Low-grade non-Hodgkin lymphoma (NHL) (i.e., small lymphocytic lymphoma, follicular center lymphoma [grade 1 or 2], marginal zone lymphoma, or B-cell lymphoma), with the following criteria:

      • Failed ≥ 1 prior chemotherapy regimen or ASCT
      • Documented chemosensitive or stable, non-bulky disease prior to transplant, defined as < 20% bone marrow involvement AND lymph node size < 3 cm in axial diameter
      • Received ≤ 3 prior chemotherapy regimens (monoclonal antibody therapy and involved-field radiotherapy are not considered a prior regimen)
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
    • Mantle cell lymphoma, with the following:

      • Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
      • Responsive or stable disease to most recent prior therapy
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
    • Intermediate-grade NHL (i.e., follicular center lymphoma [grade 3] or diffuse large cell lymphoma), meeting the following criteria:

      • Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
      • Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
    • Hodgkin lymphoma, with the following:

      • Relapsed after prior ASCT OR after ≥ 2 combination chemotherapy regimens and ineligible for ASCT
      • Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
    • Peripheral T-cell NHL, with the following:

      • Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
      • Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
  • Myeloproliferative syndrome with poor risk features, meeting 1 of the following criteria:

    • < 55 years old AND Lille score of 1
    • Lille score of 2
    • HgB < 10 g/dL AND abnormal karyotype
  • High-risk disease, with 1 of the following:

    • Age 40-72 years
    • Any age AND deemed to be at significantly increased risk of morbidity and death following a standard, myeloablative unrelated donor stem cell transplant (e.g., received extensive prior therapy, including ASCT)
  • HLA-matched unrelated donor available, with 1 of the following:

    • 8/8 match at HLA-A, B, C, or DR loci by high-resolution genotyping
    • Single allelic mismatch at either the HLA-B or HLA-C loci donor by high-resolution molecular typing

      • No single allelic mismatch at HLA-A or HLA-DR loci
  • KPS 80-100%
  • Adapted weighted Charlson Comorbidity Index < 3
  • Serum creatinine ≤ 2.0 mg/dL
  • AST or ALT < 3 times upper limit of normal (ULN)
  • Total bilirubin < 1.5 times ULN
  • LVEF ≥ 45%
  • DLCO > 50%
  • No hypoxia at rest with oxygen saturation < 92% on room air (corrected with bronchodilator therapy)
  • No other severe pulmonary function abnormalities
  • No HIV infection
  • No active hepatitis B or C infection that, in the opinion of a gastroenterologist or the transplant committee, places the patient at moderate to high risk for developing severe hepatic disease
  • No active opportunistic infection (e.g., fungal pneumonia, tuberculosis, or viral infection)
Both
40 Years to 72 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00818961
CDR0000630617, BMTGG-NSH-756
No
Northside Hospital, Inc.
Northside Hospital, Inc.
Blood and Marrow Transplant Group of Georgia
Principal Investigator: Scott R. Solomon, MD Blood and Marrow Transplant Group of Georgia
Northside Hospital, Inc.
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP