Rasburicase and Allopurinol in Treating Patients With Hematologic Malignancies

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial studies how well giving rasburicase together with allopurinol works in treating patients with hematologic malignancies. Rasburicase may reduce the level of uric acid in the blood. Allopurinol may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known which dose of rasburicase is more effective in treating hematologic malignancies when given together with or without allopurinol.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To prospectively evaluate the efficacy, as defined by uric acid response rate, of 2 different single low doses of rasburicase followed by allopurinol in 2 treatment arms. SECONDARY OBJECTIVES: I. To estimate the proportion of patients requiring additional doses of rasburicase to maintain a uric acid level =< 7.5mg/dL on day 2 through day 6. II. To identify differential characteristics of the patients who do not respond to treatment. III. To measure the area under the plasma uric acid concentration-time curve (AUC) from baseline (day 1) to day 7, time to plasma uric acid level less than or equal to 7.5mg/dL. IV. To evaluate the rate of patients requiring hemodialysis (HD) V. To evaluate the safety of low single-doses of rasburicase. VI. To evaluate the rate of patients expressing a doubling of serum creatinine. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive 1.5mg of rasburicase intravenously (IV) over 30 minutes on day 1* and allopurinol orally (PO) once daily (QD) on days 1-6. ARM II: Patients receive 3 mg of rasburicase IV over 30 minutes on day 1* and allopurinol PO QD on days 1-6. NOTE: *Patients with serum uric acid >= 7.5mg/dl also receive rasburicase IV on days 2-3. After completion of study treatment, patients are followed up at 30 days.

Official Title
-----------------
Efficacy and Safety of Two Comparable Single Low Doses of Rasburicase Followed by Allopurinol in Adult Patients With Malignancy

Conditions
-----------------
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), 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), Blastic Phase Chronic Myelogenous Leukemia, Contiguous Stage II Adult Burkitt Lymphoma, de Novo Myelodysplastic Syndromes, Noncontiguous Stage II Adult Burkitt Lymphoma, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Adult Burkitt Lymphoma, Stage I Adult Burkitt Lymphoma, Stage III Adult Burkitt Lymphoma, Stage IV Adult Burkitt Lymphoma, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: rasburicase
* Drug: allopurinol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) status of 0-3 Active leukemia and Burkitt leukemia/lymphoma treated in-house that puts them at risk for tumor lysis syndrome (TLS) Serum uric acid level >= 7.5mg/dL and high risk for TLS as defined by: A diagnosis of acute myeloid leukemia (AML), or A diagnosis of blast-phase chronic myeloid leukemia (CML), or A diagnosis of high-grade myelodysplastic syndrome (MDS) with >= 10% blast bone marrow blast involvement, or Acute lymphoblastic leukemia (ALL), or Burkitt leukemia/lymphoma Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure Exclusion Criteria: History of asthma History of severe or life threatening atopic allergy Hypersensitivity to uricases Known prior sensitivity to allopurinol Known glucose-6-phosphate dehydrogenase (G6PD) deficiency Recent prior history of uricolytic therapy defined as therapy within the last 7 days

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (1.5mg rasburicase)<br>Patients receive 1.5mg of rasburicase IV over 30 minutes on day 1 and allopurinol PO QD on days 1-6. | Drug: rasburicase<br>* Given IV<br>* Other names: recombinant urate oxidase;Drug: allopurinol<br>* Given PO<br>* Other names: Zyloprim;|
| Experimental: Arm II (3 mg rasburicase)<br>Patients receive 3 mg of rasburicase IV over 30 minutes on day 1 and allopurinol PO QD on days 1-6. | Drug: rasburicase<br>* Given IV<br>* Other names: recombinant urate oxidase;Drug: allopurinol<br>* Given PO<br>* Other names: Zyloprim;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Obtaining a Uric Acid Level =< 7.5mg/dL | The proportion of patients able to achieve and/or maintain a uric acid level =< 7.5mg/dL for each treatment arm. | Within 24 hours of rasburicase treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Requiring Additional Doses of Rasburicase to Maintain a Uric Acid Level =< 7.5mg/dL | Count of partcicpants requiring additional doses of rasburicase to maintain a uric acid level =< 7.5mg/dL by treatment arm. | Up to day 7 | 
| Baseline White Blood Cell Count by Response | The mean baseline white blood cell count of patients with a complete response (CR) (patients who achieved uric acid level =< 7.5mg/dL) and no CR (patients with uric acid level > 7.5mg/dL). | Up to day 7 | 
| Area Under the Plasma Uric Acid Concentration-time Curve (AUC) From Baseline (Day 1) to Day 7 | The mean area under the plasma uric acid concentration-time curve (AUC) from baseline (Day 1) to Day 7 | Up to day 7 | 
| Safety of Low Single-doses of Rasburicase. | The number of patients with any adverse events . | up to day 7 | 
| Number of Patients Experiencing a Doubling of Serum Creatinine | Count of participants experiencing a doubling of serum creatinine | up to day 6 |