Rasburicase in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer or Other Disease Undergoing Donor Stem Cell Transplant

NCT ID: NCT00513474

Last Updated: 2017-05-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-01-31
• Study Completion Date: 2013-02-12

Brief Summary

RATIONALE: Rasburicase may be an effective treatment for graft-versus-host disease caused by a donor stem cell transplant.

PURPOSE: This clinical trial is studying how well rasburicase works in preventing graft-versus-host disease in patients with hematologic cancer or other disease undergoing donor stem cell transplant.

Detailed Description

OBJECTIVES:

Primary

• To evaluate the incidence and severity of acute graft-vs-host disease (GVHD) in rasburicase-treated patients who will undergo myeloablative human leukocyte antigen (HLA)-matched related or unrelated donor allogeneic peripheral blood hematopoietic stem cell transplantation (SCT) for hematologic malignancies and compare these outcomes with those of historical controls.

Secondary

• To evaluate the efficacy (in terms of reduction of uric acid levels) and safety of rasburicase in patients undergoing myeloablative allogeneic SCT.
• To evaluate the graft-versus-host and host-versus-graft immune responses in rasburicase-treated patients.

OUTLINE: This is a multicenter study.

Patients receive a conventional myeloablative conditioning regimen consisting of high doses of cyclophosphamide, busulfan, and etoposide, with or without total-body irradiation. Depending on the preparative regimen selected, the conditioning of recipients will take a total of 6 to 7 days. On day 0, patients will receive filgrastim (G-CSF)-mobilized HLA-matched, related, or unrelated donor allogeneic peripheral blood stem cells (unmanipulated). Patients will receive standard graft-vs-host disease prophylaxis consisting of cyclosporine or tacrolimus and methotrexate or sirolimus. Patients will receive rasburicase IV over 30 minutes, beginning on the first day of conditioning therapy, for 5 consecutive days. If after 5 days of rasburicase the patient's uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.

Blood is obtained on day 0 and then at 14, 28, and 42 days post-transplant for immunologic studies, including quantitative analysis to follow the recovery of T cells, B cells, natural killer cells, dendritic cells (DC), and monocytes using flow cytometry (FCM); phenotypic analysis of T cells, DC and monocytes by FCM; lymphocyte activation analysis: CD3, CD4, CD8, CD25 2. CD3, CD8, CD71, CD69; DC analysis: CD45, CD14, DR, CD86, CD80 2. CD45, CD14, CD40, CD11c; and in vitro functional studies such as mixed lymphocyte reaction (MLR) and cell-mediated lysis (CML) to assess for the graft-versus-host and host-versus-graft responses. Peripheral blood is collected for chimerism studies on days 28 and 100 post-transplant.

After completion of study treatment, patients are followed periodically.

Conditions

Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

Rasburicase Group

Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator's discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant's uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.

Group Type: EXPERIMENTAL

busulfan

Intervention Type: DRUG

Busulfan 3.2 mg/kg/day from day -7 to day -4 as standard of care for myeloablative (bone marrow depletion) conditioning at the investigator's discretion

cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion

cyclosporin-A

Intervention Type: DRUG

Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion

etoposide

Intervention Type: DRUG

Etoposide as standard of care for myeloablative conditioning at the investigator's discretion

methotrexate

Intervention Type: DRUG

Methotrexate 1.5 mg/kg/day on days -3, -2, and -1 as standard of care for GVHD prophylaxis at the investigator's discretion

rasburicase

Intervention Type: DRUG

Rasburicase 0.20 mg/kg intravenous infusion over 30 minutes for 5 to 7 days

sirolimus

Intervention Type: DRUG

Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion

tacrolimus

Intervention Type: DRUG

Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion

allogeneic hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

total-body irradiation

Intervention Type: RADIATION

Total body irradiation 13.2 Gy over 8 fractions from day -7 to day - 4 for myeloablative conditioning at the investigator's discretion

fludarabine

Intervention Type: DRUG

Fludarabine 40 mg/m\^2/day from day -6 to day -3 as myeloablative conditioning at the investigator's discretion

Control Group

Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.

Group Type: OTHER

busulfan

Intervention Type: DRUG

Busulfan 3.2 mg/kg/day from day -7 to day -4 as standard of care for myeloablative (bone marrow depletion) conditioning at the investigator's discretion

cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion

cyclosporin-A

Intervention Type: DRUG

Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion

etoposide

Intervention Type: DRUG

Etoposide as standard of care for myeloablative conditioning at the investigator's discretion

methotrexate

Intervention Type: DRUG

Methotrexate 1.5 mg/kg/day on days -3, -2, and -1 as standard of care for GVHD prophylaxis at the investigator's discretion

sirolimus

Intervention Type: DRUG

Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion

tacrolimus

Intervention Type: DRUG

Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion

allogeneic hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

total-body irradiation

Intervention Type: RADIATION

Total body irradiation 13.2 Gy over 8 fractions from day -7 to day - 4 for myeloablative conditioning at the investigator's discretion

fludarabine

Intervention Type: DRUG

Fludarabine 40 mg/m\^2/day from day -6 to day -3 as myeloablative conditioning at the investigator's discretion

allopurinol

Intervention Type: DRUG

Allopurinol per institutional guidelines

Interventions

busulfan

Busulfan 3.2 mg/kg/day from day -7 to day -4 as standard of care for myeloablative (bone marrow depletion) conditioning at the investigator's discretion

Intervention Type: DRUG

cyclophosphamide

Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion

Intervention Type: DRUG

cyclosporin-A

Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion

Intervention Type: DRUG

etoposide

Etoposide as standard of care for myeloablative conditioning at the investigator's discretion

Intervention Type: DRUG

methotrexate

Methotrexate 1.5 mg/kg/day on days -3, -2, and -1 as standard of care for GVHD prophylaxis at the investigator's discretion

Intervention Type: DRUG

rasburicase

Rasburicase 0.20 mg/kg intravenous infusion over 30 minutes for 5 to 7 days

Intervention Type: DRUG

sirolimus

Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion

Intervention Type: DRUG

tacrolimus

Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion

Intervention Type: DRUG

allogeneic hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

total-body irradiation

Total body irradiation 13.2 Gy over 8 fractions from day -7 to day - 4 for myeloablative conditioning at the investigator's discretion

Intervention Type: RADIATION

fludarabine

Fludarabine 40 mg/m\^2/day from day -6 to day -3 as myeloablative conditioning at the investigator's discretion

Intervention Type: DRUG

allopurinol

Allopurinol per institutional guidelines

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Non-Hodgkin lymphoma or Hodgkin lymphoma (relapsed or refractory disease)
• Chronic lymphocytic leukemia (received more than one previous treatment regimen)
• Acute myelogenous or lymphoblastic leukemia (AML/ALL) (high-risk disease, in first complete remission [CR1] or subsequent remission, or primary refractory disease)
• Chronic myelogenous leukemia in tyrosine-kinase resistant chronic phase, accelerated or blast phase, or primary refractory disease
• Myelodysplastic syndromes in International Prognostic Scoring System (IPSS) high-intermediate or high-risk groups
• Other hematologic disorders for which allogeneic stem cell transplantation is appropriate (e.g., myelofibrosis)
• Patients who have relapsed after standard autologous and/or allogeneic bone marrow transplant are eligible
• Must be receiving filgrastim (G-CSF)-mobilized related or unrelated donor allogeneic peripheral blood stem cells

• Patients receiving hematopoietic stem cells of any other sources such as a marrow graft or umbilical cord blood will not be eligible for this study
• Donor must be HLA-genotypically or phenotypically 6 of 6 antigen matched (at the A, B, DR loci) related or unrelated

PATIENT CHARACTERISTICS:

• Patients with a "currently active" second malignancy other than non-melanoma skin cancers can only be registered if survival from the second malignancy is expected to be more than 1 year
• Ejection fraction ≥ 45% by either radioisotope Multiple Gated Acquisition Scan (MUGA) scan or Echocardiogram (ECHO)
• Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) ≥ 50% of predicted with no symptomatic pulmonary disease
• Mini Mental Status Exam Score ≥ 20
• Patients must have an expected life expectancy of at least 3 months
• Patients with symptomatic visceral, blood stream or nervous system opportunistic infection are eligible if the infection has been appropriately treated and controlled

• Patients with a fungal infection must have had treatment for at least one month and must have proof of regression of the infection prior to enrollment
• Patients may be on antibiotics at the time of transplant

Exclusion Criteria

• Human Immunodeficiency Virus (HIV) infection
• Uncontrolled diabetes mellitus
• Active congestive heart failure from any cause

• Previous history of congestive heart failure allowed
• Active angina pectoris
• Oxygen-dependent obstructive pulmonary disease
• Failure to demonstrate adequate compliance with medical therapy and follow-up
• Known history of Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency or history of hemolysis indicative of G6PD deficiency

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Bimalangshu Dey

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bimalangshu R. Dey, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Countries

United States

References

Yeh AC, Brunner AM, Spitzer TR, Chen YB, Coughlin E, McAfee S, Ballen K, Attar E, Caron M, Preffer FI, Yeap BY, Dey BR. Phase I study of urate oxidase in the reduction of acute graft-versus-host disease after myeloablative allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014 May;20(5):730-4. doi: 10.1016/j.bbmt.2014.02.003. Epub 2014 Feb 12.

Reference Type: RESULT

PMID: 24530972 (View on PubMed)

Other Identifiers

MGH-07-071

Identifier Type: -

Identifier Source: secondary_id

DFCI-07-071

Identifier Type: -

Identifier Source: secondary_id

CDR0000558480

Identifier Type: -

Identifier Source: org_study_id