Donor Stem Cell Transplant, Pentostatin, and Total-Body Irradiation in Treating Patients With Hematological Cancer

This study has been withdrawn prior to enrollment.
(Screenings yielded inadequate eligible subjects to enroll.)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Nebraska
ClinicalTrials.gov Identifier:
NCT00816413
First received: December 31, 2008
Last updated: June 17, 2013
Last verified: June 2013
  Purpose

RATIONALE: Giving low doses of chemotherapy and total-body irradiation before a donor peripheral blood 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. Removing the T cells from the donor cells before transplant and giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects of giving a donor stem cell transplant after pentostatin and total-body irradiation and to see how well it works in treating patients with hematological cancer.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Myelodysplastic Syndromes
Nonmalignant Neoplasm
Drug: cyclosporine
Drug: mycophenolate mofetil
Drug: pentostatin
Genetic: cytogenetic analysis
Genetic: fluorescence in situ hybridization
Genetic: protein analysis
Other: flow cytometry
Other: immunoenzyme technique
Other: laboratory biomarker analysis
Other: reduced-intensity transplant conditioning procedure
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation (PBSC)
Radiation: total-body irradiation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: T Cell-Reduced Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplantation With Pentostatin and Low-Dose Total Body Irradiation

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • Severe transplant-related toxicity (grade III-IV adverse events) as assessed by NCI CTCAE v2.0 [ Time Frame: before day 100 ] [ Designated as safety issue: Yes ]
  • Stable donor engraftment [ Time Frame: by day 70 ] [ Designated as safety issue: No ]
  • Mortality [ Time Frame: at day 100 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Incidence of grade III-IV acute graft-versus-host disease [ Time Frame: at day 100 ] [ Designated as safety issue: Yes ]
    An interim analysis will be performed after the accrual of each five patients (i.e., three interim analyses and 1 final analysis) has reached day 100.


Enrollment: 0
Study Start Date: September 2008
Study Completion Date: February 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: cyclosporine
    2 mg/kg IV over 2 hours every 12 hours starting at 0700 on days -1, 0, and +1 (total of six doses).
    Drug: mycophenolate mofetil
    15 mg/kg orally twice a day starting day 0 until day +27 then stopped without tapering in the absence of aGVHD then tapered over two months in the absence of aGVHD. Doses will be rounded to the nearest 250 mg.
    Drug: pentostatin
    4 mg/m2/d IV over 30 minutes daily x 3 days, (days -10, -9, -8)to begin ten days prior to stem cell infusion (Day 0).
    Genetic: cytogenetic analysis
    At days +28 and +70 post-transplant, patients' blood will be evaluated for CD3 and overall WBC chimerism.
    Genetic: fluorescence in situ hybridization
    Mixed chimerism is defined as the detection of 95% or less donor T cells (CD3+), expressed as a proportion of the total T cell and WBC population as measured by DNA.
    Genetic: protein analysis
    Blood samples will be at baseline(day -11 or before) , days -8 and -1, prior to transplant on day 0, then weekly (days +7, +14, +21 and +28) post-transplant through day +28. Five ml's of blood will be drawn at each collection through a central line using heparinized vaccutainers. Samples will be spun down at 1200 g and plasma aspirated and stored in -80 oC until analyzed for the ELISA Assays being done for research purposes in this protocol.
    Other: flow cytometry
    Peripheral blood Peripheral blood flow cytometry for immunophenotyping including Th/c1 and Th/c2 subsets, mitogens (PHA, PWM), NK and LAK function studies, DCs, apoptosis assay of tumor cells, and lymphocyte subsets (CD4, CD8, CD19, CD56
    Other: immunoenzyme technique
    Peripheral blood for immunophenotyping including Th/c1 and Th/c2 subsets, mitogens (PHA, PWM), NK and LAK function studies, DCs, apoptosis assay of tumor cells, and lymphocyte subsets (CD4, CD8, CD19, CD56
    Other: laboratory biomarker analysis
    Donor mononuclear cells from the stem cell product (SCP) obtained with apheresis will be analyzed for surface markers, including CD3, CD4, CD8, CD19, CD14, CD56, TCR+CD8+ cells, Th/c1 and Th/c2, Fas and FasL, and DCs, as well as for apoptosis
    Other: reduced-intensity transplant conditioning procedure

    Allopurinol 300 mg orally once daily x 10 days, to begin one day prior to treatment with Pentostatin (day -11 to day -2) .

    Pentostatin 4 mg/m2/d IV over 30 minutes daily x 3 days, (days -10, -9, -8)to begin ten days prior to stem cell infusion (Day 0) .

    Pre and Post Pentostatin Hydration: 1000ml Normal Saline IV over 2 hours pre each dose of Pentostatin and 1000ml Normal Saline IV over 4 hours post each dose of Pentostatin on days -10, -9, -8.

    Pre Pentostatin Recommended Antiemetics: Ondansetron 32 mg IV over 30 minutes to be given 30 min. before each dose of Pentostatin on days -10, -9, -8. Alternative ondansetron equivalent or other ancillary antiemetics may be used at the discretion of the treating physician.

    Pred Forte Eye Drops: two drops in each eye every 4 hours while awake x 7 days after starting Pentostatin (day -10 to day -4).

    Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    Each patient will receive up to four IV infusions administered over 30 minutes of donor T cells at increasing cell doses given at intervals.
    Procedure: peripheral blood stem cell transplantation (PBSC)
    PBSC are infused intravenously either by infusion or IV push on day 0 through a secure intravenous access (i.e. the double-lumen central catheter place pre transplant) according to institutional guidelines.
    Radiation: total-body irradiation
    2.0 GY will be administered on day -1. Total-body irradiation (TBI) will consist of 2.0 GY at 8-12cGy/min via 6MV photons delivered AP/PA fields, without lung blocks or via lateral fields with lucite compensator along the head and neck region. TLD (thermal luminescent dosimetry) will be used to verify dose uniformity. It is anticipated that TBI will be given on day -1; however, the timing of TBI administration may be altered by factors beyond the control of the Principal Investigator because of the delivery of unrelated donor stem cells.
Detailed Description:

OBJECTIVES:

Primary

  • To determine the safety of pentostatin and low-dose total body irradiation followed by T-cell-reduced unrelated donor peripheral blood stem cell transplantation, in terms of regimen-related toxicity, in patients with hematological malignancies.
  • To evaluate the efficacy of this regimen, measured as engraftment rate and establishment of donor hematopoietic chimerism, in these patients.

Secondary

  • To determine the incidence of acute and chronic graft-versus-host disease in patients treated with this regimen.

OUTLINE:

  • Reduced-intensity preparative regimen: Patients receive pentostatin IV over 30 minutes once daily on days -10 to -8 and undergo low-dose total-body irradiation on day -1.
  • Unrelated donor peripheral blood stem cell transplantation (PBSCT): Patients undergo T-cell-reduced donor PBSCT on day 0.
  • Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours twice daily on days -1, 0, and 1 and then orally twice daily on days 2-70 followed by a taper in the absence of GVHD. Patients also receive oral mycophenolate mofetil twice daily on days 0-27 followed by a taper.

Patients undergo bone marrow aspirate and biopsies and blood sample collection periodically for laboratory studies. Samples are analyzed for cytokines (i.e., IL-6, TNF-γ, IL-1β, and IL-10) by ELISA; phenotypic, molecular, and functional analysis of immunologic reconstitution markers (i.e., PHA, IL-2, IL-4, IL-10, IL-12, Fas, FasL, TNF, TGF-β, and IFN-γ) by flow cytometry; and cytogenetics by FISH.

After completion of study treatment, patients are followed periodically.

  Eligibility

Ages Eligible for Study:   19 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of a confirmed hematological malignancy that has relapsed or is at high risk for relapsing, including any of the following:

    • Acute myeloid leukemia (AML) meeting any of the following criteria:

      • Antecedent hematologic disorder
      • Therapy related
      • Primary induction failure
      • In first complete remission (CR1) with poor-risk cytogenetics, as defined by the following:

        • del(5q)/-5
        • del(7q)/-7
        • abn(3q)
        • t(6;9)
        • del(20q)
        • del(17p)
        • +13
        • Complex karyotype
        • t(9;22) = 11q23 rearrangement
      • In second complete remission (CR2) or greater
    • Acute lymphoblastic leukemia meeting any of the following criteria:

      • In CR1 with WBC > 50,000/mm³ at diagnosis
      • In CR1 with poor-risk cytogenetics (i.e., t[9;22], t[1;19], t[4;11]) AND meets at least 1 of the following criteria:

= 19-75 years of age AND received prior high-dose chemotherapy, total-body irradiation (TBI), or a radiation dose that precludes administration of 12 Gy of TBI = 50-75 years of age = 19-75 years of age with hematopoietic stem cell transplantation (HSCT) comorbidity index ≥ 3

  • CNS or testicular involvement at diagnosis
  • No CR within 4 weeks of initial treatment
  • Primary induction failure
  • In CR2 or greater

    • Myelodysplastic syndromes meeting the following criteria:
  • Intermediate-2 or high-risk category as determined by International Prognostic Scoring System
  • Not considered a candidate for intensive or standard chemotherapy or HSCT

    • Chronic myelogenous leukemia meeting any of the following criteria:
  • First chronic phase AND < 40 years of age
  • First chronic phase AND no hematologic response after 3 months of imatinib mesylate therapy
  • First chronic phase AND never achieved a complete cytogenetic response during imatinib mesylate therapy
  • First chronic phase AND loss of previously documented response
  • Accelerated phase
  • Blast crisis phase

    • Chronic myeloproliferative disorder (i.e., polycythemia vera, essential thrombocythemia, myelofibrosis)
  • Bone marrow blasts > 5% and/or other evidence of progression to acute leukemia

    • Chronic myelomonocytic leukemia
    • Severe aplastic anemia
  • Failed prior antithymocyte globulin and cyclosporine immunosuppressive therapy

    • Mantle cell lymphoma meeting any of the following criteria:
  • In CR1
  • In first partial remission (PR1)
  • In CR 2 or greater
  • In second PR (PR2) or greater

    • Indolent non-Hodgkin lymphoma OR chronic lymphocytic leukemia meeting either of the following criteria:
  • In CR 2 or greater
  • In PR 2 or greater

    • Lymphoblastic lymphoma
  • In CR1 or greater

    • Must have minimal residual disease as defined by either of the following:

      • No more than 5% blasts in blood and/or bone marrow (in patients with acute leukemia/MDS)
      • No bulky adenopathy (> 5 cm masses) and/or < 20% bone marrow involvement by lymphoma (in patients with lymphoma)
    • No progressive disease within 8 weeks of most recent prior therapy OR within 12 weeks of prior autologous HSCT
    • No active CNS malignancy (i.e., known positive CSF cytology or parenchymal lesions visible by CT scan or MRI)
    • HLA-matched unrelated peripheral blood stem cell donor available

      • Meets the University of Nebraska Medical Center's or the National Marrow Donor Program's criteria for donors
      • Matched at 7/8 or 8/8 HLA-A, B, C, or DRβ1 loci by molecular typing
  • If match is not at allele level, suitability for donation requires discussion with and approval by the principal investigator

    • Not an identical twin

PATIENT CHARACTERISTICS:

  • Karnofsky performance status 60-100%
  • Creatinine clearance ≥ 55 mL/min
  • Total bilirubin ≤ 2 times upper limit of normal (ULN) (unless due to Gilbert's disease or malignancy)
  • ALT and AST ≤ 4 times ULN
  • DLCO ≥ 40%
  • FEV1/FVC ratio ≥ 50% of predicted
  • Cardiac ejection fraction ≥ 40%
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • Not receiving supplementary continuous oxygen
  • No NYHA grade II-IV cardiac disease
  • HIV negative
  • No evidence of active hepatitis B (i.e., positive HBsAg and/or positive HBeAg or high copy number on quantitative RNA testing) or hepatitis C
  • No active uncontrolled infection or immediate life-threatening condition
  • No uncontrolled medical illnesses (e.g., uncontrolled systemic hypertension or diabetes)

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Prior cytoreductive chemotherapy or irradiation to areas of bulky disease allowed, as determined by the primary physician in consultation with the study investigators
  • No other concurrent anti-tumor therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00816413

Locations
United States, Nebraska
UNMC Eppley Cancer Center at the University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198-6805
Sponsors and Collaborators
University of Nebraska
Investigators
Principal Investigator: Robert Bociek, MD University of Nebraska
  More Information

No publications provided

Responsible Party: University of Nebraska
ClinicalTrials.gov Identifier: NCT00816413     History of Changes
Other Study ID Numbers: 164-07, P30CA036727, UNMC-16407
Study First Received: December 31, 2008
Last Updated: June 17, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Nebraska:
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
adult acute myeloid leukemia in remission
recurrent adult acute myeloid leukemia
secondary acute myeloid leukemia
adult acute lymphoblastic leukemia in remission
recurrent adult acute lymphoblastic leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
chronic myelomonocytic leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
essential thrombocythemia
polycythemia vera
primary myelofibrosis
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
stage III adult lymphoblastic lymphoma
stage IV adult lymphoblastic lymphoma
aplastic anemia
chronic eosinophilic leukemia

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Lymphoma
Leukemia
Syndrome
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease
Pathologic Processes
Mycophenolate mofetil
Mycophenolic Acid
Pentostatin
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Adenosine Deaminase Inhibitors

ClinicalTrials.gov processed this record on September 22, 2014