Clinical trial NCT00782379: Combination Chemotherapy, Donor Stem Cell Transplant, Tacrolimus, Mycophenolate Mofetil, and Cyclophosphamide in Treating Patients With Hematologic Cancer
Official title: A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients With Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Lymphoma
Myelodysplastic Syndromes
Keywords: 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 Hodgkin 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 IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult Hodgkin 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
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult Hodgkin lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell 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 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
accelerated phase chronic myelogenous leukemia
adult acute lymphoblastic leukemia in remission
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)
chronic myelomonocytic leukemia
chronic phase chronic myelogenous leukemia
recurrent adult acute myeloid leukemia
refractory chronic lymphocytic leukemia
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
prolymphocytic leukemia
Lead sponsor: Northside Hospital, Inc.
Sponsor class: OTHER
First posted: 2008-10-31
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy, such as fludarabine, busulfan, and cyclophosphamide, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving high-dose cyclophosphamide together with tacrolimus and mycophenolate mofetil after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well combination chemotherapy works when given together with a donor stem cell transplant, followed by tacrolimus, mycophenolate mofetil, and high-dose cyclophosphamide, in treating patients with high-risk hematologic cancer.

Detailed description: OBJECTIVES:

Primary

* To estimate the incidence of graft rejection and severe graft-versus-host disease after myeloablative HLA-mismatched peripheral blood stem cell transplantation (PBSCT) from first-degree relatives in patients with high-risk hematologic malignancies.

Secondary

* To estimate overall survival, relapse, non-relapse mortality, and event-free survival in these patients.
* To characterize additional hematologic and non-hematologic toxicities of myeloablative haploidentical PBSCT.
* To characterize donor hematopoietic chimerism in peripheral blood stem cells after PBSCT.

OUTLINE:

* Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -2, busulfan IV over 3 hours on days -7 to -4, and cyclophosphamide IV over 1-2 hours on days -3 and -2.
* Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo infusion of unmanipulated peripheral blood stem cells on day 0.
* Post-transplant regimen: Patients receive high-dose cyclophosphamide IV over 1-2 hours on days 3 and 4, tacrolimus IV over 24 hours or orally twice daily on days 5-180, and oral mycophenolate mofetil 3 times daily on days 5-34 followed by a taper to day 90. Treatment continues in the absence of disease progression or clinically significant graft-vs-host disease.

After completion of PBSCT, patients are followed periodically for 1 year.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of one of the following high-risk hematologic malignancies:

  * Chronic myelogenous leukemia meeting one of the following criteria:

    * Disease in chronic phase and resistant to available tyrosine kinase inhibitors
    * Disease in accelerated phase
    * Disease with blast crisis that has entered into a second chronic phase after induction chemotherapy
  * Acute myelogenous leukemia meeting the following criteria:

    * Marrow blasts \< 5% but persistence of minimal residual disease by flow cytometry, cytogenetics, or FISH
    * Must meet one of the following criteria:

      * Disease in second or subsequent complete remission
      * Primary induction chemotherapy failure with disease subsequently entering complete remission
      * Disease in first complete remission with poor-risk cytogenetics or arising from preceding hematological disease
  * Myelodysplastic syndrome meeting at least one of the following criteria:

    * Treatment-related
    * Monosomy 7 or complex cytogenetics
    * International prognostic scoring system score ≥ 1.5
    * Chronic myelomonocytic leukemia
  * Acute lymphocytic leukemia or lymphoblastic lymphoma meeting the following criteria:

    * Marrow blasts \< 5% but persistence of minimal residual disease by flow cytometry, cytogenetics, or FISH
    * Must meet one of the following criteria:

      * Disease in second or subsequent complete remission
      * Acute lymphocytic leukemia with poor-risk karyotype \[e.g., t(9;22) or bcr-abl fusion, t(4;11), or other MLL translocation\] and in first complete remission
  * Chronic lymphocytic leukemia or prolymphocytic leukemia meeting both of the following criteria:

    * Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy including purine analogs
    * In the opinion of the transplant physician, unlikely to benefit from reduced intensity transplantation due to the presence of one or more high-risk features (i.e., bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy)
  * Hodgkin or non-Hodgkin lymphoma (including low-grade, mantle cell, and intermediate-grade/diffuse disease) meeting the following criteria:

    * Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy or autologous transplantation
    * In the opinion of the transplant physician, unlikely to benefit from reduced intensity transplantation due to the presence of one or more high-risk features (i.e., bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy) NOTE: A new classification scheme for adult non-Hodgkin lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
* No available matched related or unrelated donor OR a matched related or unrelated donor will not be available in the time frame necessary to perform a transplant
* Availability of a first-degree relative (parent, child, sibling) matched at 3/6-5/6 loci (HLA-A, -B, -DR)

  * Donor must be willing to donate mobilized peripheral blood stem cells
  * No positive HLA crossmatch in the host-vs-graft direction or high titer donor-specific antibodies

PATIENT CHARACTERISTICS:

* Karnofsky performance status 70-100%
* Bilirubin \< 2 mg/dL (unless due to hemolysis, Gilbert syndrome, or primary malignancy)
* Creatinine \< 2 mg/dL OR creatinine clearance ≥ 40 mL/min
* Not pregnant
* Fertile patients must use effective contraception
* LVEF (Left ventriculr ejection fraction) ≥ 45%
* FEV_1 and forced vital capacity ≥ 50% predicted
* No HIV positivity
* No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment and follow-up

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No immunosuppressive agents ≤ 24 hours after completion of post-transplant cyclophosphamide (including steroids as antiemetics)

Primary outcomes:
measure: Incidence of Graft Rejection for Patients at Day 100
timeFrame: Day 100
measure: Number of Patients Who Experienced Severe Graft-versus-host Disease (GVHD)(Grade 3 or 4)
timeFrame: Day 100
Secondary outcomes:
measure: Overall Survival at Day 100
timeFrame: Day 100
measure: Non-relapse Mortality at 1 Year After Peripheral Blood Stem Cell Transplantation (PBSCT)
timeFrame: 1 year
measure: Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 30 Post-transplantation
timeFrame: Day 30
measure: Non-relapse Mortality at Day 100 After Peripheral Blood Stem Cell Transplantation (PBSCT)
timeFrame: Day 100
measure: Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 60 Post-transplantation
timeFrame: Day 60
measure: Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 90 Post-transplantation
timeFrame: Day 90
measure: Overall Survival at 12 Months
timeFrame: 12 months
measure: Disease Free Survival at 12 Months
timeFrame: 12 months
measure: Disease Free Survival at Day 100
timeFrame: Day 100
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Blood and Marrow Transplant Group of Georgia
state: Georgia
Study officials:
affiliation: Blood and Marrow Transplant Group of Georgia
name: Scott R. Solomon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Blood and Marrow Transplant Group of Georgia
name: H. Kent Holland, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Blood and Marrow Transplant Group of Georgia
name: Asad Bashey, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Blood and Marrow Transplant Group of Georgia
name: Lawrence E. Morris, MD
role: PRINCIPAL_INVESTIGATOR
References: