Clinical trial NCT00513474: Rasburicase in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer or Other Disease Undergoing Donor Stem Cell Transplant
Official title: Rasburicase to Prevent Graft -Versus-Host Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Myeloproliferative Disorders
Graft Versus Host Disease
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Keywords: 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)
adult acute myeloid leukemia with t(8;21)(q22;q22)
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
previously treated myelodysplastic syndromes
primary myelofibrosis
atypical chronic myeloid leukemia, BCR-ABL1 negative
chronic eosinophilic leukemia
chronic myelomonocytic leukemia
de novo myelodysplastic syndromes
myelodysplastic/myeloproliferative neoplasm, unclassifiable
refractory hairy cell leukemia
refractory multiple myeloma
secondary acute myeloid leukemia
secondary myelodysplastic syndromes
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
First posted: 2007-08-08
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD)
timeFrame: Up to 71 months
Secondary outcomes:
measure: Uric Acid Levels
timeFrame: Pre-transplant Day -7 to Day -1 and Post-transplant Day 0 to Day 6
measure: Number of Participant With Adverse Events (AE)
timeFrame: Up to 71 months
measure: Graft-versus-host and Host-versus-graft Immune Responses
timeFrame: Days -2, 0, and Days 14, 21 and 35 days post-transplant
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Bimalangshu R. Dey, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.