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Chronic Myeloproliferative DisordersPhase 1/2NCT00816413

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

A Phase 1/2 study testing cyclosporine, mycophenolate mofetil and pentostatin in people with Chronic Myeloproliferative Disorders and Leukemia, run by University of Nebraska.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 19 to 75 years
What is being tested?
cyclosporine, mycophenolate mofetil and pentostatin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
Sep 2008to Feb 2010
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 19 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Inclusion Criteria • 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 CR2 or greater In second PR (PR2) or greater

Indolent non-Hodgkin lymphoma OR chronic lymphocytic leukemia meeting either of the following criteria:

In CR2 or greater In PR2 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 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%Prior cytoreductive chemotherapy or irradiation to areas of bulky disease allowed, as determined by the primary physician in consultation with the study investigators

Exclusion Criteria No CR within 4 weeks of initial treatment No other concurrent anti-tumor therapy Not pregnant or nursing (fertile patients must use effective contraception) Not receiving supplementary continuous oxygen No NYHA grade II-IV cardiac disease HIV positive Active hepatitis B (i.e., positive HBsAg and/or positive HBeAg or high copy number on quantitative RNA testing) or hepatitis C Active uncontrolled infection or immediate life-threatening condition Uncontrolled medical illnesses (e.g., uncontrolled systemic hypertension or diabetes)

About this study

Official title: T Cell-Reduced Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplantation With Pentostatin and Low-Dose Total Body Irradiation

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.

Read the 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.

Being tested
cyclosporine, mycophenolate mofetil, pentostatin, cytogenetic analysis, fluorescence in situ hybridization
Keywords
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
Medical subject headings
Myeloproliferative Disorders, Leukemia, Lymphoma, Myelodysplastic Syndromes, Neoplasms, Congenital Abnormalities, Leukemia, Myeloid, Acute, Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • cyclosporineDrug

    Also called Gengraf, Neoral, and Sandimmune

    2 mg/kg IV over 2 hours every 12 hours starting at 0700 on days -1, 0, and +1 (total of six doses).

  • mycophenolate mofetilDrug

    Also called CellCept

    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.

  • pentostatinDrug

    Also called Nipent

    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).

  • cytogenetic analysisGenetic

    At days +28 and +70 post-transplant, patients' blood will be evaluated for CD3 and overall WBC chimerism.

  • fluorescence in situ hybridizationGenetic

    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.

  • protein analysisGenetic

    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.

  • flow cytometryOther

    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

  • immunoenzyme techniqueOther

    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

  • laboratory biomarker analysisOther

    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

  • reduced-intensity transplant conditioning procedureOther

    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).

  • nonmyeloablative allogeneic hematopoietic stem cell transplantationProcedure or surgery

    Each patient will receive up to four IV infusions administered over 30 minutes of donor T cells at increasing cell doses given at intervals.

  • peripheral blood stem cell transplantation (PBSC)Procedure or surgery

    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.

  • total-body irradiationRadiation

    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.

Study groups in NCT00816413
Study groupRoleWhat they receive
Donor Stem Cell Transplant, Pentostatin & Total-Body Irradiation for Hematological CancerExperimentalThis 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.
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Severe transplant-related toxicity

    Severe transplant-related toxicity (grade III-IV adverse events) as assessed by NCI CTCAE v2.0

    Measured: before day 100

  2. Stable donor engraftment

    Stable donor engraftment

    Measured: by day 70

  3. Mortality

    Death

    Measured: at day 100

Secondary outcomes (1)

  1. Incidence of grade III-IV acute graft-versus-host disease

    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.

    Measured: at day 100

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Jan 2009 (estimated)
  2. Study startSep 2008
  3. Primary completionFeb 2010
  4. Study completionFeb 2010

Why it stopped: Screenings yielded inadequate eligible subjects to enroll.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00816413
Sponsor's protocol ID
0164-07-FB
Other IDs
P30CA036727
Status last verified
Aug 2023
First submitted
31 Dec 2008
Last updated
14 Aug 2023
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing cyclosporine, mycophenolate mofetil and pentostatin in people with Chronic Myeloproliferative Disorders and Leukemia, run by University of Nebraska.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 14 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Severe transplant-related toxicity (time frame: before day 100). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00816413.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2023.

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