Clinical Trials /

Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

NCT01028716

Description:

This phase II trial studies how well donor peripheral blood stem cell (PBSC) transplant works in treating patients with hematologic malignancies. Cyclophosphamide when added to tacrolimus and mycophenolate mofetil is safe and effective in preventing severe graft-versus-host disease (GVHD) in most patients with hematologic malignancies undergoing transplantation of bone marrow from half-matched (haploidentical) donors. This approach has extended the transplant option to patients who do not have matched related or unrelated donors, especially for patients from ethnic minority groups. The graft contains cells of the donor's immune system which potentially can recognize and destroy the patient's cancer cells (graft-versus-tumor effect). Rejection of the donor's cells by the patient's own immune system is prevented by giving low doses of chemotherapy (fludarabine phosphate and cyclophosphamide) and total-body irradiation before transplant. Patients can experience low blood cell counts after transplant. Using stem cells and immune cells collected from the donor's circulating blood may result in quicker recovery of blood counts and may be more effective in treating the patient's disease than using bone marrow.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Burkitt Lymphoma
  • Follicular Lymphoma
  • Marginal Zone Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
  • Official Title: Nonmyeloablative Hematopoietic Cell Transplantation (HCT) for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors: A Phase II Trial of Peripheral Blood Stem Cells (PBSC) as the Donor Source

Clinical Trial IDs

  • ORG STUDY ID: 2372.00
  • SECONDARY ID: NCI-2009-01433
  • SECONDARY ID: 2372
  • SECONDARY ID: 2372.00
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT01028716

Conditions

  • Acute Biphenotypic Leukemia
  • Acute Erythroid Leukemia in Remission
  • Acute Leukemia in Remission
  • Acute Megakaryoblastic Leukemia
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Acute Myeloid Leukemia in Remission
  • Acute Myeloid Leukemia With FLT3/ITD Mutation
  • Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM
  • Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2); GATA2, MECOM
  • Acute Myeloid Leukemia With Multilineage Dysplasia
  • Acute Myeloid Leukemia With t(6;9) (p23;q34.1); DEK-NUP214
  • Acute Undifferentiated Leukemia
  • Adult Acute Lymphoblastic Leukemia in Complete Remission
  • B Acute Lymphoblastic Leukemia With t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1)
  • B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
  • Burkitt Lymphoma
  • Childhood Acute Lymphoblastic Leukemia in Complete Remission
  • DS Stage II Plasma Cell Myeloma
  • DS Stage III Plasma Cell Myeloma
  • Myelodysplastic Syndrome
  • Recurrent Anaplastic Large Cell Lymphoma
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Follicular Lymphoma
  • Recurrent Hodgkin Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma
  • Secondary Acute Myeloid Leukemia
  • T Lymphoblastic Lymphoma

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (nonmyeloablative HCT, TBI)
FilgrastimFilgrastim XM02, Filgrastim-sndz, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tbo-filgrastim, Tevagrastim, ZarxioTreatment (nonmyeloablative HCT, TBI)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (nonmyeloablative HCT, TBI)
Mycophenolate MofetilCellcept, MMFTreatment (nonmyeloablative HCT, TBI)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (nonmyeloablative HCT, TBI)

Purpose

This phase II trial studies how well donor peripheral blood stem cell (PBSC) transplant works in treating patients with hematologic malignancies. Cyclophosphamide when added to tacrolimus and mycophenolate mofetil is safe and effective in preventing severe graft-versus-host disease (GVHD) in most patients with hematologic malignancies undergoing transplantation of bone marrow from half-matched (haploidentical) donors. This approach has extended the transplant option to patients who do not have matched related or unrelated donors, especially for patients from ethnic minority groups. The graft contains cells of the donor's immune system which potentially can recognize and destroy the patient's cancer cells (graft-versus-tumor effect). Rejection of the donor's cells by the patient's own immune system is prevented by giving low doses of chemotherapy (fludarabine phosphate and cyclophosphamide) and total-body irradiation before transplant. Patients can experience low blood cell counts after transplant. Using stem cells and immune cells collected from the donor's circulating blood may result in quicker recovery of blood counts and may be more effective in treating the patient's disease than using bone marrow.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To demonstrate that use of PBSC in place of marrow as the source of lymphocytes and stem
      cells for nonmyeloablative transplants from related, haploidentical donors will not result in
      unacceptable rates of high-grade acute or chronic GVHD, non-relapse mortality or relapse
      compared to historical data on nonmyeloablative transplants from unrelated donors.

      SECONDARY OBJECTIVES:

      I. Estimates of the rates of neutrophil and platelet recovery, number of red blood cell (RBC)
      and platelet transfusions, incidences of graft failure, transplant-related toxicities,
      disease-free survival and overall survival.

      OUTLINE:

      Patients receive fludarabine intravenously (IV) over 30-60 minutes daily on days -6 through
      -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo
      total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell
      transplant on day 0. Patients then receive tacrolimus IV once daily or orally (PO) twice
      daily (BID) on days 5-180 (may be continued if active GVHD is present), mycophenolate mofetil
      IV or PO thrice daily (TID) on days 5-35 (may be continued if GVHD present), and filgrastim
      IV beginning on day 5 until the absolute neutrophil count (ANC) is >= 1,000/mm^3 for three
      consecutive days.

      Treatment continues in the absence of disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nonmyeloablative HCT, TBI)ExperimentalPatients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV beginning on day 5 until the ANC is >= 1,000/mm^3 for three consecutive days.
  • Cyclophosphamide
  • Fludarabine Phosphate
  • Mycophenolate Mofetil
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Molecular based human leukocyte antigen (HLA) typing will be performed for the HLA-A,
             -B, -Cw, -DRB1 and -DQB1 loci to the resolution adequate to establish haplo-identity;
             a minimum match of 5/10 is required; an unrelated donor search is not required for a
             patient to be eligible for this protocol if the clinical situation dictates an urgent
             transplant; clinical urgency is defined as 6-8 weeks from referral or low-likelihood
             of finding a matched, unrelated donor

          -  Acute leukemias (includes T lymphoblastic lymphoma); remission is defined as < 5%
             blasts with no morphological characteristics of acute leukemia (e.g., Auer rods) in a
             bone marrow with > 20% cellularity, peripheral blood counts showing ANC > 1000/ul,
             including patients in complete remission with incomplete platelet recovery (CRp); if
             the marrow has < 20% cellularity due to treatment related cytotoxicity, but still has
             < 5% blasts, an exception may be made to include this patient up to principal
             investigator (PI) discretion

          -  Acute lymphoblastic leukemia in high risk first complete remission (CR1) as defined by
             at least one of the following:

               -  Adverse cytogenetics including but not limited to t(9;22), t(1;19), t(4;11),
                  mixed lineage leukemia (MLL) rearrangements

               -  White blood cell counts > 30,000/mcL

               -  Patients over 30 years of age

               -  Time to complete remission > 4 weeks

               -  Presence of extramedullary disease

               -  Minimal residual disease

               -  Other risk factors determined by the patient's attending physician to be high
                  risk features requiring transplantation

          -  Acute myelogenous leukemia in high risk CR1 as defined by at least one of the
             following:

               -  Greater than 1 cycle of induction therapy required to achieve remission

               -  Preceding myelodysplastic syndrome (MDS)

               -  Presence of fms-like tyrosine kinase receptor-3 (Flt3) abnormalities

               -  French-American-British (FAB) M6 or M7 leukemia, or

               -  Adverse cytogenetics for overall survival such as:

                    -  Those associated with MDS

                    -  Complex karyotype (>= 3 abnormalities); or

                    -  Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with
                       other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)],
                       t(11;19)(q23;p13.1)]

               -  Other risk factors determined by the patient's attending physician to be high
                  risk features requiring transplantation

          -  Acute leukemias in second (2nd) or subsequent remission

          -  Biphenotypic/undifferentiated leukemias in first (1st) or subsequent complete
             remission (CR)

          -  High-risk MDS status-post cytotoxic chemotherapy

          -  Burkitt's lymphoma: second or subsequent CR

          -  Chemotherapy-sensitive (at least stable disease) large cell, mantle cell or Hodgkin's
             lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and
             are ineligible for an autologous transplant

          -  Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at
             least two prior therapies (excluding single agent Rituxan)

          -  Multiple myeloma (MM) stage II or III patients who have progressed after an initial
             response to chemotherapy or autologous hematopoietic stem cell transplantation (HSCT)
             or MM patients with refractory disease who may benefit from tandem
             autologous-nonmyeloablative allogeneic transplant

          -  Left ventricular ejection fraction at rest must be >= 35%

          -  Bilirubin =< 2.5 mg/dL

          -  Alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) < 5 x ULN

          -  Alkaline phosphatase < 5 x ULN

          -  Serum creatinine within normal range for age, or if serum creatinine outside normal
             range for age, then renal function (creatinine clearance or glomerular filtration rate
             [GFR]) > 40 mL/min/1.73m^2

          -  Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), diffusion
             capacity of carbon monoxide (DLCO) (diffusion capacity) >= 40% predicted (corrected
             for hemoglobin); if unable to perform pulmonary function tests, then oxygen (O2)
             saturation > 92% on room air

          -  Karnofsky/Lansky score >= 60%

          -  Patients who have received a prior allogeneic HSCT and who have either rejected their
             grafts or who have become tolerant of their grafts with no active GVHD requiring
             immunosuppressive therapy

          -  Patients will undergo standard pre-transplant work-up as dictated by standard practice
             guidelines the results of which may be used for screening for this study

          -  DONOR: Donors must be HLA-haploidentical first-degree relatives of the patient;
             eligible donors include biological parents, siblings, or children, or half-siblings

          -  DONOR: Age >= 12 years

          -  DONOR: Weight >= 40 kg

          -  DONOR: Ability of donors < 18 years of age to undergo apheresis without use of a
             vascular access device; vein check must be performed and verified by an apheresis
             nurse prior to arrival at the Seattle Cancer Care Alliance (SCCA)

          -  DONOR: Donors must meet the selection criteria as defined by the Foundation for the
             Accreditation of Cell Therapy (FACT) and will be screened per the American Association
             of Blood Banks (AABB) guidelines

        Exclusion Criteria:

          -  HLA-matched or single allele-mismatched donor able to donate

          -  Pregnancy or breast-feeding

          -  Current uncontrolled bacterial, viral or fungal infection (currently taking medication
             with evidence of progression of clinical symptoms or radiologic findings)

          -  Patients with primary idiopathic myelofibrosis

          -  DONOR: Positive anti-donor HLA antibody
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cumulative incidence of non-relapse mortality, defined as death without evidence of disease progression
Time Frame:Up to 1 year
Safety Issue:
Description:Scored according to the National Cancer Institute criteria. The time to onset of limited and extensive chronic graft versus host disease will be recorded.

Secondary Outcome Measures

Measure:Donor cell engraftment
Time Frame:Up to day 84 post-transplant
Safety Issue:
Description:Donor chimerism in the T-cell (CD3-positive) and granulocyte (CD33-positive) fractions of sorted peripheral blood greater or equal to 50%.
Measure:Infections
Time Frame:Up to 7 years
Safety Issue:
Description:Reported by anatomic site, date of onset, organism and resolution, if any.
Measure:Neutrophil recovery
Time Frame:Up to day 84 post-transplant
Safety Issue:
Description:Achievement of an absolute neutrophil count greater or equal to 500/mm^3 for three consecutive measurements on different days. The first of the three days will be designated the day of neutrophil recovery.
Measure:Platelet recovery
Time Frame:Up to day 84 post-transplant
Safety Issue:
Description:The first day of a sustained platelet count > 20,000/mm^3 with no platelet transfusions in the preceding seven days.
Measure:Primary graft failure
Time Frame:At day 84
Safety Issue:
Description:Defined as < 5% donor CD3 chimerism. Chimerism will be measured by short tandem repeat-polymerase chain reaction on peripheral blood sorted into CD3 and CD33 cell fractions.
Measure:Progression-free survival
Time Frame:Time interval to relapse/recurrence, to death or to last follow-up, assessed for up to 7 years
Safety Issue:
Description:Defined as the minimum time interval to relapse/recurrence, to death or to last follow-up.
Measure:Secondary graft failure
Time Frame:Up to day 84 post-transplant
Safety Issue:
Description:Initial recovery followed by neutropenia with < 5% donor chimerism. If no chimerism assays were performed and absolute neutrophil count is less than 500/mm^3, then it will be counted as a secondary graft failure.
Measure:Toxicity of treatment regimen
Time Frame:Up to day 90
Safety Issue:
Description:Assessed by Common Terminology Criteria for Adverse Events version 3.0. The incidence of all adverse events greater or equal to grade 3 will be determined.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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