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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00513474
First Posted: August 8, 2007
Last Update Posted: May 25, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Bimalangshu Dey, Massachusetts General Hospital
  Purpose

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.


Condition Intervention Phase
Chronic Myeloproliferative Disorders Graft Versus Host Disease Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Neoplasms Drug: busulfan Drug: cyclophosphamide Drug: cyclosporin-A Drug: etoposide Drug: methotrexate Drug: rasburicase Drug: sirolimus Drug: tacrolimus Procedure: allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Radiation: total-body irradiation Drug: fludarabine Drug: allopurinol Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Rasburicase to Prevent Graft -Versus-Host Disease

Resource links provided by NLM:


Further study details as provided by Bimalangshu Dey, Massachusetts General Hospital:

Primary Outcome Measures:
  • Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD) [ Time Frame: Up to 71 months ]

    aGVHD severity was determined using International Bone Marrow Transplant Registry (IBMTR) scale stage and grade of the skin, liver and gut. Stage 1: Skin=maculopapular rash <25% of body surface; Liver=Bilirubin 2-3 mg/dL and Gut=500-999 mL diarrhea/day or peristent nausea with histologic evidence of GvHD. Stage 2: Skin=maculopapular rash 25-50% of body surface; Liver=Bilirubin 3.1-6 mg/dL and Gut=1000-1499 mL diarrhea/day. Stage 3: Skin=maculopapular rash >50% of body surface; Liver=Bilirubin 6.1-15 mg/dL and Gut=≥1500 mL diarrhea/day. Stage 4: Skin=generalized erythroderma with bulla formation; Liver=Bilirubin >15 mg/dL and Gut=severe abdominal pain.

    Grade 1: Stage 1-2 rash; no liver or gut involvement. Grade II: Stage 3 rash, or stage 1 liver involvement, or stage 1 gut involvement. Grade III: None to stage 3 skin rash with stage 2-3 liver, or stage 2-4 gut involvement. Grade IV: Stage 4 skin rash, or stage 4 liver involvement.



Secondary Outcome Measures:
  • Uric Acid Levels [ Time Frame: Pre-transplant Day -7 to Day -1 and Post-transplant Day 0 to Day 6 ]
    Blood was collected and analyzed at a laboratory for serum uric acid levels reported in milligrams(mg)/deciliter(dL). Data is presented for those participants who experienced Grade II to IV aGVHD and those participants who did not experience Grade II to IV aGVHD at pre-transplant and post-transplant.

  • Number of Participant With Adverse Events (AE) [ Time Frame: Up to 71 months ]
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.

  • Graft-versus-host and Host-versus-graft Immune Responses [ Time Frame: Days -2, 0, and Days 14, 21 and 35 days post-transplant ]
    Laboratory tests such as limited dilution assay (LDA) were to be performed to assess graft-versus-host and host-versus-graft immune responses.


Enrollment: 46
Study Start Date: January 2008
Study Completion Date: February 12, 2013
Primary Completion Date: February 12, 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: 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
Drug: cyclophosphamide
Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion
Drug: cyclosporin-A
Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion
Drug: etoposide
Etoposide as standard of care for myeloablative conditioning at the investigator's discretion
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
Drug: rasburicase
Rasburicase 0.20 mg/kg intravenous infusion over 30 minutes for 5 to 7 days
Drug: sirolimus
Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion
Drug: tacrolimus
Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion
Procedure: allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Radiation: 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
Drug: fludarabine
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.
Drug: 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
Drug: cyclophosphamide
Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion
Drug: cyclosporin-A
Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion
Drug: etoposide
Etoposide as standard of care for myeloablative conditioning at the investigator's discretion
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
Drug: sirolimus
Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion
Drug: tacrolimus
Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion
Procedure: allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation Radiation: 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
Drug: fludarabine
Fludarabine 40 mg/m^2/day from day -6 to day -3 as myeloablative conditioning at the investigator's discretion
Drug: allopurinol
Allopurinol per institutional guidelines

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Patients with hematologic malignancies for whom conventional myeloablative allogeneic stem cell transplantation is deemed clinically appropriate and who are eligible for conventional myeloablative allogeneic stem cell transplantation on treatment plans/protocols, including any of the following:

    • 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:

Inclusion criteria:

  • 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00513474


Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114-2617
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: Bimalangshu R. Dey, MD, PhD Massachusetts General Hospital
  More Information

Publications:
Responsible Party: Bimalangshu Dey, Associate Professor of Medicine, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00513474     History of Changes
Other Study ID Numbers: CDR0000558480
MGH-07-071
DFCI-07-071
First Submitted: August 6, 2007
First Posted: August 8, 2007
Results First Submitted: February 27, 2017
Results First Posted: April 11, 2017
Last Update Posted: May 25, 2017
Last Verified: April 2017

Keywords provided by Bimalangshu Dey, Massachusetts General Hospital:
graft versus host disease
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
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 adult T-cell leukemia/lymphoma
recurrent cutaneous T-cell non-Hodgkin 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 mycosis fungoides/Sezary syndrome
recurrent small lymphocytic lymphoma
splenic marginal zone lymphoma
Waldenström macroglobulinemia
recurrent adult acute lymphoblastic leukemia
refractory chronic lymphocytic leukemia
recurrent adult acute myeloid leukemia
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)

Additional relevant MeSH terms:
Lymphoma
Syndrome
Leukemia
Neoplasms
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Graft vs Host Disease
Myeloproliferative Disorders
Plasmacytoma
Myelodysplastic-Myeloproliferative Diseases
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease
Pathologic Processes
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Cyclophosphamide
Methotrexate