Clinical Trials /

Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation, and Donor Bone Marrow Transplant Followed by Donor Natural Killer Cell Therapy, Mycophenolate Mofetil, and Tacrolimus in Treating Patients With Hematologic Cancer

NCT00789776

Description:

This phase I/II trial studies the side effects and best dose of donor natural killer (NK) cell therapy and to see how well it works when given together with fludarabine phosphate, cyclophosphamide, total-body irradiation, donor bone marrow transplant, mycophenolate mofetil, and tacrolimus in treating patients with hematologic cancer. Giving chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells. It may also 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. Giving an infusion of the donor's T cells (donor lymphocyte infusion) may help the patient's immune system see any remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving mycophenolate mofetil and tacrolimus after the transplant may stop this from happening.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Fludarabine Phosphate</span>, <span class="go-doc-concept go-doc-intervention">Cyclophosphamide</span>, Total-Body Irradiation, and Donor <span class="go-doc-concept go-doc-intervention">Bone Marrow Transplant</span> Followed by Donor Natural Killer Cell Therapy, <span class="go-doc-concept go-doc-intervention">Mycophenolate Mofetil</span>, and <span class="go-doc-concept go-doc-intervention">Tacrolimus</span> in Treating Patients With Hematologic Cancer

Title

  • Brief Title: Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation, and Donor Bone Marrow Transplant Followed by Donor Natural Killer Cell Therapy, Mycophenolate Mofetil, and Tacrolimus in Treating Patients With Hematologic Cancer
  • Official Title: A Phase I/II Study Evaluating the Safety and Efficacy of Adding a Single Prophylactic Donor Lymphocyte Infusion (DLI) of Natural Killer Cells Early After Nonmyeloablative, HLA-Haploidentical Hematopoietic Cell Transplantation - A Multi Center Trial
  • Clinical Trial IDs

    NCT ID: NCT00789776

    ORG ID: 2230.00

    NCI ID: NCI-2010-00106

    Trial Conditions

    Acute Lymphoblastic Leukemia

    Acute Myeloid Leukemia

    Aggressive Non-Hodgkin Lymphoma

    Diffuse Large B-Cell Lymphoma

    Previously Treated Myelodysplastic Syndrome

    Recurrent Chronic Lymphocytic Leukemia

    Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive

    Recurrent Indolent Adult Non-Hodgkin Lymphoma

    Recurrent Mantle Cell Lymphoma

    Recurrent Plasma Cell Myeloma

    Recurrent Small Lymphocytic Lymphoma

    Refractory Chronic Lymphocytic Leukemia

    Refractory Hodgkin Lymphoma

    Refractory Small Lymphocytic Lymphoma

    Waldenstrom Macroglobulinemia

    Refractory Plasma Cell Myeloma

    Trial Interventions

    Drug Synonyms Arms
    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, CYCLOPHOSPHAMIDE, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719 Treatment (non-myeloablative transplant)
    Fludarabine Phosphate 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, FLUDARABINE PHOSPHATE, Oforta, SH T 586 Treatment (non-myeloablative transplant)
    Mycophenolate Mofetil Cellcept, MMF, MYCOPHENOLATE MOFETIL Treatment (non-myeloablative transplant)
    Tacrolimus FK 506, Fujimycin, Prograf, Protopic, TACROLIMUS Treatment (non-myeloablative transplant)

    Trial Purpose

    This phase I/II trial studies the side effects and best dose of donor natural killer (NK)
    cell therapy and to see how well it works when given together with fludarabine phosphate,
    cyclophosphamide, total-body irradiation, donor bone marrow transplant, mycophenolate
    mofetil, and tacrolimus in treating patients with hematologic cancer. Giving chemotherapy,
    such as fludarabine phosphate and cyclophosphamide, and total-body irradiation before a
    donor bone marrow transplant helps stop the growth of cancer cells. It may also 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. Giving an infusion of the donor's
    T cells (donor lymphocyte infusion) may help the patient's immune system see any remaining
    cancer cells as not belonging in the patient's body and destroy them (called
    graft-versus-tumor effect). Sometimes the transplanted cells from a donor can make an immune
    response against the body's normal cells. Giving mycophenolate mofetil and tacrolimus after
    the transplant may stop this from happening.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. Identification of the maximal feasible dose of NK cells that can be infused one week
    after nonmyeloablative, human leukocyte antigen (HLA)-haploidentical hematopoietic cell
    transplant (HCT). (Phase I)

    SECONDARY OBJECTIVES:

    Once the maximal feasible dose has been identified, accrual will be limited to the cohort
    containing this cell dose to determine:

    I. Incidence of relapse. (Phase II)

    II. Incidence of grades III-IV acute graft-versus-host disease (GVHD). (Phase II)

    III. Incidence of non-relapse mortality. (Phase II)

    OUTLINE: This is a phase I, dose-escalation study of donor NK cell therapy followed by a
    phase II study.

    CONDITIONING: Patients receive fludarabine intravenously (IV) over 30 minutes on days -6 to
    -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total-body
    irradiation on day -1.

    DONOR BONE MARROW TRANSPLANTATION: Patients undergo donor bone marrow transplantation on day
    0.

    POST-TRANSPLANTATION IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on
    day 3 and mycophenolate mofetil orally (PO) thrice daily (TID) on days 4 to 40, followed by
    a taper until day 84 in the absence of GVHD. Patients also receive tacrolimus IV
    continuously or IV once daily (QD) over 1-2 hours or PO twice daily (BID) on days 4 to 84,
    followed by a taper until day 180 in the absence of GVHD.

    DONOR NK CELL INFUSION: Patients undergo donor lymphocyte infusion of NK cells on day 7.

    After completion of study treatment, patients are followed up at 6 months, 1 year, 1.5
    years, and then every year thereafter.

    Trial Arms

    Name Type Description Interventions
    Treatment (non-myeloablative transplant) Experimental CONDITIONING: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total-body irradiation on day -1. DONOR BONE MARROW TRANSPLANTATION: Patients undergo donor bone marrow transplantation on day 0. POST-TRANSPLANTATION IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3 and mycophenolate mofetil PO TID on days 4 to 40, followed by a taper until day 84 in the absence of GVHD. Patients also receive tacrolimus IV continuously or IV QD over 1-2 hours or PO BID on days 4 to 84, followed by a taper until day 180 in the absence of GVHD. NK CELL INFUSION: Patients undergo donor lymphocyte infusion of NK cells on day 7. Cyclophosphamide, Fludarabine Phosphate, Mycophenolate Mofetil, Tacrolimus

    Eligibility Criteria

    Inclusion Criteria:

    - Patients with the following hematologic malignancies will be permitted although other
    diagnoses can be considered if approved by Patient Care Conference (PCC) and the
    principal investigators:

    - Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B
    cell (DLBC) NHL - a) not eligible for autologous HCT, b) not eligible for high-dose
    HCT, c) after failed autologous HCT, or d) be part of a tandem auto-allo approach for
    high risk patients

    - Mantle cell NHL must be beyond first complete response (CR)

    - Low-grade NHL with < 6 month duration of CR between courses of conventional therapy

    - Chronic lymphocytic leukemia (CLL) must have either

    - 1) Failed to meet National Cancer Institute (NCI) Working Group criteria for
    complete or partial response after therapy with a regimen containing FLU
    (fludarabine phosphate) (or another nucleoside analog, e.g.
    2-chlorodeoxyadenosine [2-CDA], pentostatin) or experience disease relapse
    within 12 months after completing therapy with a regimen containing FLU (or
    another nucleoside analog)

    - 2) Failed FLU- CY (cyclophosphamide)-rituximab (FCR) combination chemotherapy at
    any time point; or

    - 3) Have "17p deletion" cytogenetic abnormality and relapsed at any time point
    after any initial chemotherapy

    - Hodgkin lymphoma - must have received and a) failed frontline therapy, b) not be
    eligible for autologous HCT, or c) or be part of a tandem auto-allo approach for high
    risk patients

    - Multiple myeloma or plasma cell leukemia must have received more than one line of
    prior chemotherapy; consolidation of chemotherapy by autografting prior to
    nonmyeloablative HCT is permitted

    - Acute myeloid leukemia (AML) must have < 5% marrow blasts at the time of HCT

    - Acute lymphocytic leukemia (ALL) must have < 5% marrow blasts at the time of HCT

    - Chronic myeloid leukemia (CML) accepted if they are beyond chronic phase (CP)1 and if
    they have received previous myelosuppressive chemotherapy or HCT and have < 5% marrow
    blasts at time of transplant

    - Myelodysplasia (MDS)/myeloproliferative syndrome (MPS) - (> intermediate 1 [int-1]
    per International Prognostic Scoring System [IPSS]) after > or = 1 prior cycle of
    induction chemotherapy; must have < 5% marrow blasts at time of transplant

    - Waldenstrom's macroglobulinemia must have failed 2 courses of therapy

    - Patients must be expected to have disease controlled for at least 60 days after HCT

    - Patients for whom HLA-matched unrelated donor search could not be initiated or
    completed due to insurance reasons, concerns of rapidly progressive disease, and/or
    discretion of attending physician are eligible for this protocol

    - DONOR: Related, HLA-haploidentical donors who are identical for one HLA haplotype and
    mismatched for any number of HLA-A, -B, -C, DRB1 or DQB1 loci of the unshared
    haplotype

    - DONOR: Marrow will be the only allowed hematopoietic stem cell source

    - DONOR: Haploidentical donor selection will be based on standard institutional
    criteria, otherwise no specific prioritization will be made amongst the suitable
    available donors; donors will not be selected based on killer cell
    immunoglobulin-like receptor (KIR) status

    Exclusion Criteria:

    - Patients with available HLA-matched related donors

    - Patients eligible for a curative autologous HCT

    - Significant organ dysfunction that would prevent compliance with conditioning, GVHD
    prophylaxis, or would severely limit the probability of survival:

    - 1) Symptomatic coronary artery disease or ejection fraction < 35% or other
    cardiac failure requiring therapy (or, if unable to obtain ejection fraction,
    shortening fraction of < 26%); if shortening fraction is < 26% a cardiology
    consult is required with the principal investigator (PI) having final approval
    of eligibility

    - 2) Diffusion capacity of the lung for carbon monoxide (DLCO) < 40% total lung
    capacity (TLC) < 40%, forced expiratory volume in one second (FEV1) < 40% and/or
    receiving supplementary continuous oxygen; the Fred Hutchinson Cancer Research
    Center (FHCRC) study PI must approve enrollment of all patients with pulmonary
    nodules

    - 3) Liver function abnormalities: patient with clinical or laboratory evidence of
    liver disease will be evaluated for the cause of liver disease, its clinical
    severity in terms of liver function, bridging fibrosis, and the degree of portal
    hypertension; the patient will be excluded if he/she is found to have fulminant
    liver failure, cirrhosis of the liver with evidence of portal hypertension,
    alcoholic hepatitis, esophageal varices, a history of bleeding esophageal
    varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction
    evinced by prolongation of the prothrombin time, ascites related to portal
    hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic
    viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary
    disease

    - Human immunodeficiency virus (HIV) seropositive patients

    - Patients with poorly controlled hypertension despite multiple antihypertensive
    medications

    - Fertile females who are unwilling to use contraceptive techniques during and for the
    twelve months following treatment, as well as females who are pregnant or actively
    breast feeding

    - Fertile males who are unwilling to use contraceptive techniques during and for the
    twelve months following treatment

    - Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
    or those with non-hematologic malignancies (except non-melanoma skin cancers) who
    have been rendered with no evidence of disease, but have a greater than 20% chance of
    having disease recurrence within five years; this exclusion does not apply to
    patients with non-hematologic malignancies that do not require therapy

    - Active infectious disease concerns

    - Karnofsky performance score < 60 Lansky performance score < 60

    - Life expectancy severely limited by diseases other than malignancy

    - Patients with a diagnosis of chronic myelomonocytic leukemia (CMML)

    - Central nervous system (CNS) involvement with disease refractory to intrathecal
    chemotherapy

    - Patients with AML, MDS, ALL, or CML must not have presence of circulating leukemic
    blasts detected by standard pathology

    - Patients with aggressive lymphomas (such as DLBC) must not have bulky, rapidly
    progressive disease immediately prior to HCT

    - Patients who have received a prior allogeneic HCT must have no active GVHD requiring
    immunosuppressive therapy for at least 21 days prior to start of conditioning

    - DONOR: Children less than 12 years of age.

    - DONOR: Children greater than or equal to 12 years of age who have not provided
    informed assent in the presence of a parent and an attending physician who is not a
    member of the recipient's care team

    - DONOR: Children greater than or equal to 12 years of age who have inadequate
    peripheral vein access to safely undergo apheresis

    - DONOR: Donors unable or unwilling to undergo marrow harvest for the initial HCT,
    storage of autologous blood prior to marrow harvest or apheresis one week after
    marrow harvest

    - DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1
    x 10^8 nucleated cells/kg recipient ideal body weight [IBW]) for the initial HCT; the
    average nucleated cell content of harvested marrow is 22 x 10^6 nucleated cells/mL or
    220 x 10^8 nucleated cells/Liter

    - DONOR: HIV-positive donors

    - DONOR: Donors who are cross-match positive with recipient

    Minimum Eligible Age: N/A

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Dose-limiting toxicity (Phase I)

    Secondary Outcome Measures

    Acute GvHD (Phase II)

    Chronic extensive GvHD (Phase II)

    Contribution of KIR ligand alloreactivity to relapse (Phase II)

    Engraftment (Phase II)

    Evaluation of rejection (Phase II)

    NK cell infusion on post-transplant immune reconstitution (Phase II)

    Non-relapse mortality (Phase II)

    Overall survival (Phase II)

    Progression (Phase II)

    Relapse (Phase II)

    Trial Keywords