Allogeneic Hematopoietic Cell Transplantation for Patients With Busulfex-based Regimen (LCCC0510)
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.
|Chronic Myeloproliferative Disorders Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes||Biological: rabbit anti-thymocyte globulin (ATG) Biological: therapeutic allogeneic lymphocytes Drug: busulfan Drug: fludarabine phosphate Drug: tacrolimus Procedure: allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Drug: methotrexate||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Undergoing Dose-Adjusted Treatment With A Maximally Intensive Busulfex-Based Therapeutic Regimen|
- Three-year Relapse-free Survival (RFS) Rate at the Maximum Tolerated Dose Identified During Phase I of the Trial (Target AUC 6912) [ Time Frame: Three years post-transplant ]Relapse is defined as new or increased sites of disease or positive one marrow after a complete response (CR). The RFS was calculated as the percentage of patients who were alive and without relapse at 3 years
- Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: first 6 weeks or 42 days following stem cell infusion ]Dose limiting toxicity will be defined as any irreversible grade 3 or any grade 4 non-hematologic toxicity that is related to busulfan infusion and not graft vs host disease or late infection after recovery from the initial period of myelosuppression. The maximum tolerated dose (MTD) is defined as the dose with probability of dose limiting toxicity (DLT) of 0.25. The dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine and alemtuzumab plus tacrolimus for GVHD prophylaxis.
- 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 [ Time Frame: Day -15 to Day -11 ]Test doses of busulfan were administered and plasma levels were measured to determine a targeted AUC dosing estimate. The capacity is reported as the precision with which these test dose goals predicted the actual 90-hour mean AUC levels.Dose targeting precision was estimated by root mean squared error.
- Incidence of Graft vs Host Disease in Patients Between One Month and Two Years Post Transplant [ Time Frame: 100 days post transplant ]
GVHD can be mild, moderate or severe depending on the differences in tissue type between patient and donor. GVHD can be acute or chronic. 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
- Incidence of DNA Chimerism in Patients Between One Month Post Transplant [ Time Frame: 30 days post transplant ]Deoxyribonucleic acid (DNA) chimerism is a measure identifying the genetic profiles of the transplant recipient and of the donor and then evaluating the extent of mixture in the recipient's blood, bone marrow, or other tissue.
- Overall Survival [ Time Frame: Three years post-transplant ]Percentage of participants alive at 3 years post transplant
|Study Start Date:||October 2005|
|Study Completion Date:||November 2015|
|Primary Completion Date:||November 2015 (Final data collection date for primary outcome measure)|
Experimental: GVHD prophylaxis
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.
Biological: rabbit anti-thymocyte globulin (ATG)
.5 mg/kg on day -3 and 2.5 mg/kg on day -2Biological: therapeutic allogeneic lymphocytes
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 0Drug: busulfan
PK-targeted continuous IV infusion over 90 hours on Days -7 to -4.Drug: fludarabine phosphate
30 mg/m^2/day x 5 days intravenous piggyback (IVPB) over 30 minutes on Days -7 through -3Drug: tacrolimus
The suggested starting dose is 0.03 mg/kg po bid starting on day -1Procedure: allogeneic hematopoietic stem cell transplantation
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 0Procedure: peripheral blood stem cell transplantation
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 0Drug: methotrexate
5 mg/m^2 on days +1, +3 and +6
- 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)
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00448357
|United States, North Carolina|
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill|
|Chapel Hill, North Carolina, United States, 27599-7295|
|Principal Investigator:||Thomas C. Shea, MD||UNC Lineberger Comprehensive Cancer Center|