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Chronic Myeloproliferative DisordersPhase 2NCT00448201

Reduced-Intensity Busulfan and Fludarabine With or Without Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Disease

A Phase 2 study testing anti-thymocyte globulin, sargramostim and therapeutic allogeneic lymphocytes in people with Chronic Myeloproliferative Disorders and Leukemia, run by UNC Lineberger Comprehensive Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

RATIONALE: Giving low doses of chemotherapy, such as busulfan and fludarabine, before a donor stem cell transplant helps stop the growth of cancer and abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. Read more about this study

Who is it for?
Ages 10 years and older
What is being tested?
anti-thymocyte globulin, sargramostim and therapeutic allogeneic lymphocytes
Could I receive a placebo?
No, everyone receives an active treatment
How many people
71 participants
Where
1 siteUnited States
Study dates
7 Jan 2011to 23 May 2012
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 10 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

DISEASE CHARACTERISTICS:

  • Histologically confirmed diagnosis of 1 of the following:
  • Chronic lymphocytic leukemia (CLL), meeting the following criteria:
  • Absolute lymphocyte count > 5,000/mm³
  • Lymphocytes must appear morphologically mature with < 55% prolymphocytes
  • Lymphocyte phenotype with expression of CD19 and cluster of differentiation 5 (CD5)
  • Prolymphocytic leukemia (PLL), meeting the following criteria:
  • Absolute lymphocyte count > 5,000/mm³
  • More than 55% prolymphocytes
  • Morphologically diagnosed
  • Chronic myelogenous leukemia (CML), meeting the following criteria:
  • Diagnosis of CML or similar myeloproliferative disorders based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood cell (WBC) counts in peripheral blood or bone marrow
  • In first chronic phase CML and a candidate for treatment with reduced-dose busulfan
  • Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible
  • Non-Hodgkin's lymphoma (NHL), meeting the following criteria:
  • Any World Health Organization (WHO) class histologic subtype allowed
  • Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping
  • Bone marrow biopsies as sole means of diagnosis are not allowed for follicular lymphoma
  • Hodgkin's lymphoma, meeting the following criteria:
  • Any WHO class histologic subtype allowed
  • Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping
  • Multiple myeloma, meeting the following criteria:
  • Active disease requiring treatment (Durie-Salmon stages I, II, or III)
  • Acute myeloid leukemia with documented control, defined as < 10% bone marrow blasts and no circulating blasts
  • Acute lymphoblastic leukemia, meeting the following criteria:
  • In early first relapse or beyond OR in first complete remission and has 1 of the following high-risk features:
  • t(9;22) or t(4;11)
  • WBC count > 30,000/mm³ at presentation
  • Non-T-cell phenotype
  • More than 30 years of age
  • Agnogenic myeloid metaplasia/myelofibrosis
  • Patients who are transfusion dependent or who have evolving myelodysplastic or leukemic features or high-risk cytogenetic abnormalities are eligible
  • Myelodysplastic syndromes (MDS) as defined by WHO criteria
  • Meets 1 of the following criteria:
  • Over 55 years of age
  • Ineligible for busulfan-based therapy based on diminished organ function or poor performance status
  • Indolent and chemotherapy-responsive CLL, low-grade NHL, small lymphocytic lymphoma, or PLL
  • Patients who have undergone prior autologous stem cell transplantation are preferentially enrolled on clinical trial CALGB-100002, if available and patient is eligible
  • HLA-matched or mismatched related donor or HLA-matched unrelated donor available
  • HLA-identical sibling (6/6 or 9/10) (minimal serologic typing required for class I [A, B]; molecular typing required for class II (DRB1))
  • 9/10 matched unrelated donor (MUD) (molecular analysis at HLA A, B, C, DRB1, and DQB1 by high resolution typing required)
  • 5/6 MUD (molecular analysis at HLA A, B, and DRB1 required)
  • No syngeneic donors

PATIENT CHARACTERISTICS:

  • Creatinine clearance ≥ 40 mL/min
  • Bilirubin ≤ 3 times upper limit of normal (ULN)
  • aspartate aminotransferase (AST) ≤ 3 times ULN
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
  • Left ventricular ejection fraction (LVEF) ≥ 30% by multigated acquisition scan (MUGA)
  • No uncontrolled diabetes mellitus or active serious infection
  • No known hypersensitivity to Escherichia coli-derived products
  • No HIV infection
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • More than 4 weeks since prior chemotherapy, radiotherapy (except prophylactic cranial x-ray therapy), or surgery

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

    Chapel Hill, North Carolina, 27599-7295

Other trials in United States

About this study

Official title: Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment With a More Intensive Therapeutic Regimen

RATIONALE: Giving low doses of chemotherapy, such as busulfan and fludarabine, before a donor stem cell transplant helps stop the growth of cancer and abnormal cells. It also helps 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 or abnormal cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Immunosuppressive therapy may improve bone marrow function and may be an effective treatment for hematologic cancer or other disease.

PURPOSE: This clinical trial is studying the side effects and how well giving busulfan and fludarabine with or without antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer or other disease.

Read the detailed description

OBJECTIVES:

Primary

  • Determine the clinical efficacy and toxicity profiles of a nonmyeloablative preparative regimen comprising busulfan and fludarabine with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation in patients with hematologic cancers or other diseases.
  • Determine the feasibility of this regimen in these patients.
  • Establish a treatment-related mortality during the first 6 months that is less than 20% in patients treated with this regimen.

Secondary

  • Determine the response rates (disease-specific partial response and complete response) in patients treated with this regimen.
  • Determine overall and progression-free survival of patients treated with this regimen.
  • Determine the percent donor chimerism and immunologic recovery, including dendritic cell recovery, in patients treated with this regimen.
  • Determine the risk of acute and chronic graft-versus-host disease and other toxicities in patients treated with this regimen.
  • Assess the overall nonhematologic grades 3 and 4 toxicity of this regimen, including the incidence of veno-occlusive disease and pulmonary toxicity, in these patients.

OUTLINE: Patients are assigned to 1 of 4 treatment groups according to disease type and donor type.

  • Preparative regimen:
  • Group 1 (patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), IPSS (International Prognostic Scoring System score) high-risk myelodysplastic syndromes (HR MDS), or chronic myelogenous leukemia (CML) with an human leukocyte antigen (HLA)-matched related donor (MRD): Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV continuously over 48 hours on days -6 and -5.
  • Group 2 (patients with AML, ALL, IPSS HR MDS, or CML with an HLA-matched unrelated donor (MUD) or mismatched related donor (MMRD)): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on day -8.
  • Group 3 (patients with all other diseases with a MRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin as in group 2.
  • Group 4 (patients with all other disease with a MUD or MMRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on days -8 and -7.
  • Allogeneic stem cell transplantation: All patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously once daily beginning on day 5 (groups 1 and 2) or day 7 (groups 3 and 4) and continuing until blood counts recover.
  • Graft-vs-host disease (GVHD) prophylaxis: All patients receive oral tacrolimus twice daily on days -1 to 120 followed by a taper until day 180. Patients in groups 1 and 2 also receive methotrexate IV on days 1, 3, and 6.
  • Donor lymphocyte infusion (DLI): After day 120, patients with progressive disease or stable disease while off immunosuppression and with no evidence of active GVHD may receive DLI. Treatment with DLI may repeat every 8 weeks for up to 3 total infusions in the absence of disease response or GVHD.

Peripheral blood and/or bone marrow samples are collected at baseline and then at 30, 60, 90, 120, and 180 days post-transplantation. Chimerism (including the following subsets: whole blood, T-cells as defined by cluster of differentiation 3 (CD3) positivity, B-cells as defined by Cluster of Differentiation 19 (CD19) positivity, and myeloid cells as defined by Cluster of Differentiation 14 (CD14) and Cluster of Differentiation 15 (CD15) positivity is analyzed by polymerase chain reaction technology.

After restaging between Days 90 and 100 and between Days 150 to 180, patients are followed every 6 months for 1 years and then yearly for a maximum of 5 years from study entry.

Being tested
anti-thymocyte globulin, sargramostim, therapeutic allogeneic lymphocytes, busulfan, fludarabine phosphate
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), prolymphocytic leukemia, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, blastic phase chronic myelogenous leukemia, childhood acute lymphoblastic leukemia in remission, childhood acute myeloid leukemia in remission, childhood chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, de novo myelodysplastic syndromes, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma
Medical subject headings
Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma, Neoplasms, Plasma Cell, Myelodysplastic Syndromes, Congenital Abnormalities, Leukemia, Prolymphocytic

What participants receive

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

  • anti-thymocyte globulinBiological

    0.5 mg/kg on day -3, 2.5 mg/kg on day -2 (groups 2, 3 and 4) and 3 mg/kg on day -1 (group 4 only)

  • sargramostimBiological

    GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) < 1000/microliter (uL) past day 20

  • therapeutic allogeneic lymphocytesBiological

    A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10^6 cells/kg and a maximum 8 x 10^6 cells/kg will be infused on day 0

  • busulfanDrug

    6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5

  • fludarabine phosphateDrug

    fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3

  • methotrexateDrug

    Methotrexate 5 mg/m^2 per day on days +1, +3 and +6

  • tacrolimusDrug

    Suggested starting dose is 0.03 mg/kg po bid starting on Day -1

  • nonmyeloablative allogeneic hematopoietic stem cell transplantationProcedure or surgery

    Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0

  • peripheral blood stem cell transplantationProcedure or surgery

    Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0

Study groups in NCT00448201
Study groupRoleWhat they receive
Methotrexate Only ArmActive comparatorGVHD Prophylaxis with Methotrexate
Receives: Biological: sargramostim; Biological: therapeutic allogeneic lymphocytes; Drug: busulfan; Drug: fludarabine phosphate; Drug: methotrexate; Drug: tacrolimus; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation
2 Doses ATG + MethotrexateActive comparatorGVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
Receives: Biological: anti-thymocyte globulin; Biological: sargramostim; Biological: therapeutic allogeneic lymphocytes; Drug: busulfan; Drug: fludarabine phosphate; Drug: methotrexate; Drug: tacrolimus; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation
2 Doses ATGActive comparatorGVHD prophylaxis with 2 doses ATG
Receives: Biological: anti-thymocyte globulin; Biological: sargramostim; Biological: therapeutic allogeneic lymphocytes; Drug: busulfan; Drug: fludarabine phosphate; Drug: tacrolimus; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation
3 Doses ATGActive comparatorGVHD prophylaxis with 3 doses ATG
Receives: Biological: anti-thymocyte globulin; Biological: sargramostim; Biological: therapeutic allogeneic lymphocytes; Drug: busulfan; Drug: fludarabine phosphate; Drug: tacrolimus; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation

What is being measured

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

  1. Treatment-related Mortality

    Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse.

    Measured: 6 months

Secondary outcomes (4)

  1. Complete Response at 6 and 12 Months Post-transplant

    Measured: 6 and 12 months

  2. Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant

    Complete chimerism is defined as 100% donor cells detected, suggesting complete hematopoietic replacement. Mixed donor chimerism means host cells are detected in particular cells like lymphocytes. Five to 90% donor cells set the criteria for mixed chimerism (MC).

    Chimerism was not tabulated on day 30.

    Measured: Days 30, 60, and 90

  3. 5-year Disease-free Survival

    The length of time post-transplant that the patient survives without any signs or symptoms of that cancer.

    Measured: Year 5

  4. Graft-vs-host Disease at 6 Months Post-transplant

    Graft-vs-host disease (GVHD) can be mild, moderate or severe depending on the differences in tissue type between patient and donor. Its symptoms can include:

    • Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body
    • Blistering, causing the exposed skin surface to flake off in severe cases
    • Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected
    • Jaundice, or a yellowing of the skin, which can indicate liver damage
    • Excessive dryness of the mouth and throat, leading to ulcers
    • Dryness of the lungs, vagina and other surfaces

    Acute GVHD - Can occur soon after the transplanted cells begin to appear in the recipient. Acute GVHD ranges from mild, moderate or severe, and can be life-threatening if its effects are not controlled.

    Extensive chronic GVHD - Usually occurs at about three months post-transplant.

    Measured: 6 Months

Timeline

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

  1. First posted16 Mar 2007 (estimated)
  2. Study start7 Jan 2011
  3. Primary completion11 Jan 2011
  4. Study completion23 May 2012

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 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
71 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00448201
Sponsor's protocol ID
LCCC 0306
Other IDs
P30CA016086
Status last verified
May 2017
First submitted
14 Mar 2007
Last updated
30 May 2017
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing anti-thymocyte globulin, sargramostim and therapeutic allogeneic lymphocytes in people with Chronic Myeloproliferative Disorders and Leukemia, run by UNC Lineberger Comprehensive Cancer Center at 1 site in United States.

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: finished, as of the sponsor's last update on 30 May 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

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 phase mean?

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?

Yes. Results are posted in the registry (first posted 30 May 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Treatment-related Mortality (time frame: 6 months). 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 NCT00448201.

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 30 May 2017.

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