Clinical trial NCT00301912: Busulfan and Fludarabine Before Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
Official title: Phase II Study Evaluating Busulfan and Fludarabine as Preparative Therapy in Adults With Hematopoietic Disorders Undergoing Matched Unrelated Donor Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Anemia
Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Keywords: chronic phase chronic myelogenous leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
adult acute myeloid leukemia in remission
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)
recurrent adult acute myeloid leukemia
secondary acute myeloid leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
atypical chronic myeloid leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
adult acute lymphoblastic leukemia in remission
recurrent adult lymphoblastic lymphoma
anemia
refractory chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
Waldenstrom macroglobulinemia
stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma
polycythemia vera
essential thrombocythemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
relapsing chronic myelogenous leukemia
chronic eosinophilic leukemia
chronic idiopathic myelofibrosis
chronic myelomonocytic leukemia
chronic neutrophilic leukemia
noncontiguous stage II adult Burkitt lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
noncontiguous stage II marginal zone lymphoma
noncontiguous stage II small lymphocytic lymphoma
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
recurrent adult acute lymphoblastic leukemia
stage I multiple myeloma
childhood myelodysplastic syndromes
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-03-13
Enrollment: 0
Sex: ALL
Minimum age (years): 16
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as busulfan and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy with a peripheral stem cell or bone marrow transplant may allow more chemotherapy to be given so that more cancer cells are killed. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Tacrolimus and methotrexate may stop this from happening.

PURPOSE: This phase II trial is studying how well giving busulfan together with fludarabine before donor stem cell transplant works in treating patients with hematologic cancer.

Detailed description: OBJECTIVES:

Primary

* Determine the safety, in terms of treatment-related mortality at 100 days post-transplantation, of a myeloablative preparative regimen comprising busulfan and fludarabine and graft-vs-host disease (GVHD) prophylaxis comprising tacrolimus and methotrexate in patients with hematopoietic disorders undergoing matched unrelated donor stem cell transplantation.
* Determine the efficacy, in terms of overall survival at 1-year post-transplantation, in patients treated with this regimen.

Secondary

* Determine organ toxicity in patients treated with this regimen.
* Determine neutrophil and platelet recovery in patients treated with this regimen.
* Determine the incidence and severity of acute and chronic GVHD in patients treated with this regimen.

OUTLINE:

* Myeloablative preparative regimen: Patients receive busulfan IV over 2 hours every 6 hours on days -7 to -4 and fludarabine IV over 30 minutes on days -7 to -3.
* Allogeneic stem cell transplantation: Patients undergo allogeneic peripheral blood stem cell or bone marrow transplantation on day 0. Patients also receive filgrastim (G-CSF) subcutaneously daily beginning on day 7 and continuing until blood counts recover.
* Graft-vs-host disease prophylaxis: Patients receive tacrolimus IV continuously beginning on day -2 and continuing until discharged from the hospital (may convert to oral dosing administered twice daily when tolerated) and methotrexate IV over 15-30 minutes on days 1, 3, 6, and 11.

After completion of study therapy, patients are followed periodically.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following hematopoietic disorders:

  * Chronic myelogenous leukemia (CML), meeting 1 of the following criteria:

    * Chronic phase disease failing imatinib mesylate therapy

      * Progressive disease OR failed to achieve a major cytogenetic response at 1 year after initiation of therapy
    * Accelerated phase disease, meeting 1 of the following criteria:

      * Failed to achieve complete cytogenetic remission at 1 year after initiation of therapy
      * Failed to achieve any cytogenetic response at 3 or 6 months during therapy
      * Progressive disease, demonstrated by worsening cytogenetic response in 2 consecutive analyses separated by 4 weeks
    * Blast crisis with \< 10% blasts in bone marrow within 6 weeks of transplantation
  * Acute myeloid leukemia (AML), meeting 1 of the following criteria:

    * In second or greater remission
    * In first remission with poor prognosis cytogenetics \[-5, -5q, -7, -7q and ≥ 2 cytogenetic abnormalities, t(6,9), t(9,11), or Philadelphia chromosome\]
    * In hematologic remission but with persistent cytogenetic abnormalities
    * Primary refractory AML with \< 10% blasts in bone marrow within 6 weeks of transplantation
  * Myelodysplasia with \< 20% blasts in bone marrow within 6 weeks of transplantation and meeting 1 of the following criteria:

    * Advanced disease (International Prognostic Scoring System \[IPSS\] score intermediate-1, intermediate-2, or high risk)
    * Myelodysplastic syndromes (MDS) with progression to AML
    * Treatment-related AML
  * Acute lymphocytic leukemia (ALL), meeting 1 of the following criteria:

    * In second or greater remission
    * In first remission with high-risk cytogenetics \[Philadelphia chromosome; t(4,11); and -7\]
    * Primary refractory ALL with \< 10% blasts in the bone marrow
  * Severe aplastic anemia that has failed immunosuppressive therapy
  * Non-Hodgkin's lymphoma, meeting 1 of the following criteria:

    * In second or greater remission
    * Relapsed disease in a patient not eligible for autologous stem cell transplantation
  * Lymphoproliferative disease (e.g., chronic lymphocytic leukemia or Waldenstrom's macroglobulinemia), meeting 1 of the following criteria:

    * In second or greater remission
    * Relapsed disease in a patient not eligible for autologous stem cell transplantation
  * Multiple myeloma, meeting 1 of the following criteria:

    * Stage II or III disease in first or greater relapse
    * Refractory disease
    * Newly diagnosed disease with chromosome 13 abnormalities
  * Advanced myeloproliferative disease, meeting 1 of the following criteria:

    * Myelofibrosis requiring \> 2 units of packed red blood cells each month
    * Essential thrombocythemia or polycythemia rubra vera that has progressed to AML
    * Failed prior AML therapy
* No active, uncontrolled CNS leukemia
* Not eligible for autologous or mini-allogeneic transplantation
* No fully matched or single-antigen mismatched sibling donor available
* HLA-matched unrelated donor available

  * HLA typed at HLA-A, -B, -C, -DRB1 and/or -DQB1 by high-resolution techniques
  * For patients without HLA identical donors, mismatches at DQ (i.e., 8/8 match) and 1 additional mismatch at the allele level at HLA-A, -B, -C, or -DRB1 (i.e., 7/8 molecular match) allowed

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Creatinine \< 2.0 mg/dL
* Pulmonary diffusing capacity \> 40% of predicted
* Cardiac ejection fraction \> 40% by MUGA or echocardiography
* No active liver disease
* Bilirubin ≤ 2.0 mg/dL
* Alkaline phosphatase \< 3 times upper limit of normal (ULN)
* AST \< 3 times ULN
* Hepatitis C or active hepatitis B (HBV) allowed provided a liver biopsy is performed and ≤ grade 2 inflammation is present

  * Patients with active HBV viral replication must receive antiviral therapy
* HIV negative
* No ongoing active infection
* Not pregnant or nursing
* Negative pregnancy test

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* More than 3 weeks since prior chemotherapy except for hydroxyurea or imatinib mesylate
* More than 3 months since prior interferon

Primary outcomes:
measure: Treatment-related mortality in the first 100 days post-transplant
measure: Overall survival at 1 year post-transplant
Secondary outcomes:
measure: Incidence and severity of organ-specific toxicity
measure: Engraftment including neutrophil and platelet recovery and donor chimerism at 3 and 12 months post-transplant
measure: Rate of acute graft-vs-host disease (GVHD)
measure: Rate of chronic GVHD
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
Study officials:
affiliation: University of California, San Francisco
name: Thomas G. Martin, MD
role: STUDY_CHAIR
References: