Hematopoietic Cell Transplantation for Pediatric Patients With Hematologic Malignancies

NCT00795132 | Completed Phase 2 Results DMC

• 1 other identifier: HCI12073
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Leukaemia; Chronic Disease; Leukemia; Myelodysplasia; Lymphoma

Keywords

cancer; Hematologic Malignancies; Hematopoietic Cell Transplantation

Outcome Measures

Primary Outcomes (1)

• Number of High Risk Pediatric Patients With Successful Sustained Donor Engraftments

  Assessed donor engraftment in very high risk pediatric patients.

  24 months

Secondary Outcomes (2)

• Two Year Overall Survival

  24 months

• Number of Participants Who Experienced Transplantation-related Mortality (TRM)

  24 months

Study Arms (3)

Related BM PBSC

ACTIVE COMPARATOR

Bone Marrow Peripheral Blood Stem Cell (BM PBSC) from a donor related to the participant/recipient

Drug: Busulfan; Drug: Anti-Thymocyte Globulin; Drug: Fludarabine; Drug: Cyclosporine; Drug: Mycophenolate mofetil

Unrelated BM PBSC

ACTIVE COMPARATOR

Bone Marrow Peripheral Blood Stem Cell (BM PBSC) from a donor unrelated to the participant/recipient

Drug: Busulfan; Drug: Anti-Thymocyte Globulin; Drug: Fludarabine; Drug: Cyclosporine; Drug: Mycophenolate mofetil

Unrelated Blood Cord

ACTIVE COMPARATOR

Blood Cord donated from a donor unrelated to the participant/recipient

Drug: Busulfan; Drug: Anti-Thymocyte Globulin; Drug: Fludarabine; Drug: Cyclosporine; Drug: Mycophenolate mofetil

Interventions

Busulfan DRUG

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.

Also known as: Busulfex

Related BM PBSC; Unrelated BM PBSC; Unrelated Blood Cord

Anti-Thymocyte Globulin DRUG

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.

Also known as: Thymoglobulin® [Anti-thymocyte Globulin, (Rabbit)]

Related BM PBSC; Unrelated BM PBSC; Unrelated Blood Cord

Fludarabine DRUG

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.

Also known as: Fludara

Related BM PBSC; Unrelated BM PBSC; Unrelated Blood Cord

Cyclosporine DRUG

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.

Related BM PBSC; Unrelated BM PBSC; Unrelated Blood Cord

Mycophenolate mofetil DRUG

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.

Also known as: MMF, CellCept

Related BM PBSC; Unrelated BM PBSC; Unrelated Blood Cord

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may not qualify if:

• Renal: creatinine clearance \<60ml/m/1.73m2
• Hepatic: transaminases \>4x normal or total bilirubin \>2.0
• Cardiac: all patients with suspected cardiac toxicity should undergo a cardiac echo. If the shortening fraction (SF) is \<25% a measurement of ejection fraction must be obtained. Patients qualify for reduced intensity therapy if the SF is \<25% and the EF \<50%.
• Infections: Patients with responsive but unresolved invasive infections. These infections may be fungal, bacterial or other opportunistic infections. Viral infections do not meet this eligibility criteria.
• Patients must be in a CR (\<5% blasts on BM morphology, no active CNS disease, see protocol) with the following exceptions:
• AML may proceed with M2 marrow status (\<20% blasts).
• Lymphoma: residual disease must be responsive and non-bulky (\<5cm largest diameter).
• Myelodysplasia: Patients with RA, and RAEB are eligible, but RAEB-IT patients are only eligible if treated to \<5% blasts (RA) with chemotherapy.
• CML-BP must be treated to CR/CP2 to be eligible.
• Females who are pregnant
• Patients who are HIV positive or who have other progressive infections
• Organ dysfunction: patients are ineligible for the following levels of severe organ system dysfunction:
• Cardiac: Ejection fraction \<30%
• Pulmonary: Receiving continuous supplementary oxygen or any of the following: DLCO \<30%, FVC/TLC \< 30% or FEV1 \<30%
• Hepatic: patients will be excluded for hepatic synthetic dysfunction evidenced by any of the following: prolongation of the prothrombin time with an INR \>2.0, total serum bilirubin \>3, or transaminases \>10x normal.

Sponsors & Collaborators

• University of Utah: lead

Study Sites (1)

Primary Children's Medical Center

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• Pulsipher MA, Boucher KM, Wall D, Frangoul H, Duval M, Goyal RK, Shaw PJ, Haight AE, Grimley M, Grupp SA, Kletzel M, Kadota R. Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood. 2009 Aug 13;114(7):1429-36. doi: 10.1182/blood-2009-01-196303. Epub 2009 Jun 15.

  PMID: 19528536 DERIVED

MeSH Terms

Conditions

Chronic Disease; Leukemia; Anemia, Refractory, with Excess of Blasts; Lymphoma; Neoplasms; Hematologic Neoplasms

Interventions

Busulfan; Antilymphocyte Serum; thymoglobulin; fludarabine; fludarabine phosphate; Cyclosporine; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia, Refractory; Anemia; Myelodysplastic Syndromes; Bone Marrow Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Limitations and Caveats

Participants who experienced early relapse or death before engraftment were excluded from analysis.

Results Point of Contact

• Title: Dr. Michael Pulsipher
• Organization: University of Utah

michael.pulsipher@hsc.utah.edu

801-588-2680

Study Officials

• Michael Pulsipher, MD

  Primary Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2008
• First Posted: November 21, 2008
• Study Start: April 1, 2004
• Primary Completion: July 1, 2009
• Study Completion: July 1, 2009
• Last Updated: July 30, 2013
• Results First Posted: August 20, 2012

Record last verified: 2013-07

Locations

US (1)