Clinical trial NCT00795132
Conditions: Acute Leukaemia Chronic Disease Leukemia Myelodysplasia Lymphoma
Keywords: cancer Hematologic Malignancies Hematopoietic Cell Transplantation
Sponsor: University of Utah
Start date: 2004-04-01; Completion date: 2009-07-01
Enrollment: 47 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II trial of reduced intensity conditioning with Bu/Flu/ATG in pediatric patients with hematologic malignancies at high risk for transplant related mortality with standard transplantation. Patients qualify based on organ system dysfunction, active but stable infection, history of previous transplant or late stage disease. We plan to enroll 45 patients through the Pediatric Blood and Marrow Transplant Consortium (PBMTC) and anticipate that the outcome of the trial will pave the way for phase II or III disease specific protocols addressing efficacy of the approach compared to standard transplant approaches in better risk patients.

Detailed description:
Summary/Proposal: Reduced Intensity Hematopoietic Cell Transplantation for High-Risk Relapsed Pediatric Hematologic Malignancies and Patients Ineligible for Standard Transplantation We propose a phase II trial of reduced intensity conditioning with Bu/Flu/ATG in pediatric patients with hematologic malignancies at high risk for transplant related mortality with standard transplantation. Patients qualify based on organ system dysfunction, active but stable infection, history of previous transplant, or late stage disease. We plan to enroll 45 patients through the Pediatric Blood and Marrow transplant Consortium (PBMTC) and anticipate that the outcome of the trial will pave the way for phase II or III disease specific protocols addressing efficacy of the approach compared to standard transplant approaches in better risk patients.

Hypothesis High risk pediatric hematologic malignancy patients ineligible for standard myeloablative HCT undergoing reduced intensity conditioning (RIC) HCT can achieve a sustained engraftment rate \> 90% with a 100day TRM \< 30% using either bone marrow or PBSC from related or unrelated donors. High risk pediatric patients undergoing RIC-HCT using related or unrelated cord blood can achieve a sustained engraftment rate \>80% and a 100d TRM \<30%.

Rationale for Reduced Intensity Approaches in High Risk Patients There are a number patient-specific risk factors associated with increased transplant related mortality. They can be broadly placed into three categories: pretransplant organ system dysfunction, active infections at the time of transplant, and degree of pretransplant therapy (previous transplants, third or subsequent remission, etc.).

The primary objective of this study is to determine the likelihood of achieving sustained donor engraftment using reduced intensity conditioning (fludarabine/busulfan/ATG) followed by hematopoietic cell transplantation (HCT) with either cord blood, bone marrow or peripheral blood stem cells (PBMTC) in pediatric patients with hematopoietic malignancies who are at high risk of transplant related mortality (TRM) with myeloablative HCT. Patients qualify based on organ system dysfunction, active but stable infection, history of previous transplant or late stage disease. We plan to enroll 45 patients through the Pediatric Blood and Marrow Transplant Consortium (PBMTC) and anticipate that the outcome of the trial will pave the way for phase II or III disease specific protocols addressing efficacy of the approach compared to standard transplant approaches in better risk patients.

Study procedures Patients receive their conditioning regimen consisting of fludarabine, busulfan, and ATG and then receive their stem cell transplant. Patients receive immunosuppression consisting of cyclosporine and mycophenolate mofetil. Patients with persistent or progressive disease may receive donor lymphocyte infusion off protocol.

Arms: arm 1: Bone Marrow Peripheral Blood Stem Cell (BM PBSC) from a donor related to the participant/recipient arm 2: Bone Marrow Peripheral Blood Stem Cell (BM PBSC) from a donor unrelated to the participant/recipient arm 3: Blood Cord donated from a donor unrelated to the participant/recipient
Interventions: intervention 1: Busulfan intervention 2: Anti-Thymocyte Globulin intervention 3: Fludarabine intervention 4: Cyclosporine intervention 5: Mycophenolate mofetil
Intervention descriptions: intervention 1: This drug is a bifunctional alkylating agent. Busulfan is highly toxic to noncycling or slowly-cycling cells. Pharmacokinetic studies of the IV formulation in pediatrics have shown that using a dose of 0.8mg/kg IV q6 hours most patients will achieve AUC levels between 800 and 1300 uM/min, representing steady state levels between 600-900ug/ml. The manufacturer recommends higher doses, 1.1mg/kg for children less than 12kg. Because this is a reduced intensity study and infants on the study will be very heavily pretreated we will use the lower dose of 0.8mg/kg q6 hours for a total of 8 doses for all patients. intervention 2: Thymoglobulin will be administered at a dose of 2.5 mg/kg recipient body weight intravenously on each of 4 successive mornings (Days -4, -3,-2,-1) for patients receiving unrelated grafts and at a dose of 2.5mg/kg as a single dose on d-1 for patients receiving related marrow grafts. ATG is infused over a minimum of 4 hours, but is generally better tolerated over 6-8 hours. Suggested premedications are acetaminophen (10 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and methylprednisolone. The methylprednisolone should be given at a dose of

1mg/kg 30 minutes prior to the ATG, with another 1mg /kg four hours into the infusion (total 2mg/kg/d). Patients are observed continuously for possible allergic reactions throughout the infusion. intervention 3: Administration and Dosage: Fludarabine will be administered at a dose of 30 mg/m2 in 100 ml of D5W intravenously over one hour on each of six consecutive days -10 through -5 for unrelated grafts or d-7 through d-2 for related grafts. Fludarabine is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-beta-D-arabinofuranosyladenine. Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. The half-life of 2-fluoro-ara-A is approximately 10 hours. The mean total plasma clearance is 8.9 L/hr/m2 and the mean volume of distribution is 98 L/m2. Approximately 23% is excreted unchanged. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. intervention 4: Cyclosporine is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G 0 - and G

1 -phase of the cell cycle. Administration and Dosage: Cyclosporin start on day -3 initially at a dose of 2.5mg/kg IV q12 hours or 3mg/kg/dose (neoral equivalent) PO q12 hours targeting suggested troughs of 250 to 350 ng/ml. Continuous infusion cyclosporin may be allowed per institutional preference. 3x daily dosing may be used for younger children to achieve therapeutic levels. PBMTC Protocol #ONC0313 19 Continuous infusion cyclosporin may be allowed per institutional preference. intervention 5: MMF is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Administration and Dosage: Initial dosage will be IV or PO with switch to PO when tolerated. Starting doses will be 15 mg/kg/day bid (total dose 30mg/kg/d, IV same as PO dose) beginning day 0 with the first dose given approximately 4-6 hours after the stem cell infusion. This dose will stop on day +30 for patients receiving matched sibling BM/PBSC and UCB grafts, but will continue until day +40 and then taper at approximately 11%/wk over 8 weeks until patients are off at day +96.

Protocol documents: