Clinical trial NCT00448357
Conditions: Chronic Myeloproliferative Disorders Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes
Keywords: refractory multiple myeloma relapsing chronic myelogenous leukemia secondary acute myeloid leukemia stage II multiple myeloma stage III multiple myeloma 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 adult Hodgkin 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 Waldenstrom macroglobulinemia accelerated phase chronic myelogenous leukemia adult acute myeloid leukemia in remission blastic phase chronic myelogenous leukemia chronic eosinophilic leukemia chronic neutrophilic leukemia extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue nodal marginal zone B-cell lymphoma recurrent adult Burkitt 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 adult immunoblastic large cell lymphoma recurrent adult lymphoblastic lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent mantle cell lymphoma recurrent marginal zone lymphoma recurrent 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 Hodgkin 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 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) primary myelofibrosis chronic phase chronic myelogenous leukemia de novo myelodysplastic syndromes previously treated myelodysplastic syndromes prolymphocytic leukemia recurrent adult acute lymphoblastic leukemia recurrent adult acute myeloid leukemia refractory chronic lymphocytic leukemia secondary myelodysplastic syndromes stage III chronic lymphocytic leukemia stage IV chronic lymphocytic leukemia adult acute lymphoblastic leukemia in remission polycythemia vera essential thrombocythemia splenic marginal zone lymphoma recurrent mycosis fungoides/Sezary syndrome recurrent cutaneous T-cell non-Hodgkin lymphoma stage I multiple myeloma recurrent adult grade III lymphomatoid granulomatosis adult nasal type extranodal natural killer (NK)/T-cell lymphoma
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2005-10-01; Completion date: 2015-11-01
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Giving chemotherapy, such as fludarabine and busulfan, before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also 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 a monoclonal antibody, alemtuzumab, before the transplant and tacrolimus after the transplant may stop this from happening.

PURPOSE: The phase I portion of this trial identified the maximum tolerated dose of busulfan after treating 40 patients on a dose-escalation scheme. We are now treating an additional 26 patients on the phase II portion of the trial at a Pharmacokinetic (PK)-directed dose of total area under curve (AUC) 6912 micrometer (uM)-min/24 hours. We transitioned to the Phase II portion of the study in October 2009.

Detailed description:
OBJECTIVES:

Primary

* Phase I Objective: To identify the maximum tolerated dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine, ATG and methotrexate plus tacrolimus for GVHD prophylaxis
* Phase II Objective: To determine the one-year disease-free survival (DFS) rate at the maximum tolerated dose identified during Phase I of the trial (target AUC 6912)

Secondary

* Determine the overall and disease-free survival of patients treated with this regimen.
* Determine the dose-limiting toxicities of this regimen in these patients.
* Determine the capacity of test dosing of busulfan that would result in the desired area under the curve concentration exposure of patients receiving a full-dose busulfan regimen.
* Determine the incidence of graft-vs-host disease and DNA chimerism between 1 month and 2 years post-transplantation in these patients.
* Compare the overall survival (OS) and disease-free survival (DFS) rates for patients treated with Campath vs. patients treated with ATG/Methotrexate for GVHD control

OUTLINE: This is a non-randomized, open-label, parallel group study of busulfan. Patients are stratified according to donor relationship - matched related donor (MRD) vs matched unrelated donor (MUD).

* Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours once within days -15 to -10 and then IV continuously over 90 hours on days -7 to -4. Patients with a MRD also receive Methotrexate (MTX) on Days +1, +3, and +6. Patients with a MUD receive ATG on Days -3 and -2 and MTX on Days +1, +3 and +6.

Phase I portion only: Cohorts of 3-6 patients receive escalating doses of busulfan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

* Allogeneic peripheral blood stem cell transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
* Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus twice daily on days -1 to 180 or days -1 to 240.
* Donor lymphocyte infusion (DLI): Patients who do not achieve CR, do not have GVHD, and have been off immunosuppressants for at least 30 days may receive up to 3 DLIs, at least 8 weeks apart, after completion of tacrolimus.

After the completion of study treatment, patients are followed periodically for up to 5 years.

Arms: arm 1: Subjects with matched-related donors (MRDs) were treated with tacrolimus and methotrexate with or without alemtuzumab for graft vs host disease prophylaxis Subjects also receive busulfan and fludarabine .

Matched unrelated donor (MUD) or mismatched related donor (MMRD) subjects receive GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) + Methotrexate Subjects also receive busulfan, fludarabine, and tacrolimus.
Interventions: intervention 1: rabbit anti-thymocyte globulin (ATG) intervention 2: therapeutic allogeneic lymphocytes intervention 3: busulfan intervention 4: fludarabine phosphate intervention 5: tacrolimus intervention 6: allogeneic hematopoietic stem cell transplantation intervention 7: peripheral blood stem cell transplantation intervention 8: methotrexate
Intervention descriptions: intervention 1: .5 mg/kg on day -3 and 2.5 mg/kg on day -2 intervention 2: minimum total cluster of differentiation (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 intervention 3: PK-targeted continuous IV infusion over 90 hours on Days -7 to -4. intervention 4: 30 mg/m\^2/day x 5 days intravenous piggyback (IVPB) over 30 minutes on Days -7 through -3 intervention 5: The suggested starting dose is 0.03 mg/kg po bid starting on day -1 intervention 6: A minimum total CD34+ cell dose of 3 x 10\^6 cells/kg and maximum of 8 x 10\^6 cells/kg will be infused on day 0 intervention 7: minimum total CD34+ cell dose of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on day 0 intervention 8: 5 mg/m\^2 on days +1, +3 and +6

Protocol documents: