Rasburicase in Patients at High Risk for Tumor Lysis Syndrome (TLS) During Cycle-2

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01200485
• Collaborator: Sanofi (Industry)
• Enrollment: 55
• Location: 1
• Arms: 3
• Duration (Months): 63
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if using Elitek (rasburicase) for 2 cycles can help to control or prevent TLS better than 1 cycle of rasburicase and 1 cycle of allopurinol. The safety of this treatment will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Lymphoma	Drug: Rasburicase; Drug: Allopurinol	Phase 2

Detailed Description

Study Drugs:

Rasburicase is designed to help decrease or prevent the high level of uric acid that may occur during the beginning of chemotherapy. A high level of uric acid results from TLS and can lead to kidney failure.

Allopurinol is designed to help block uric acid. It is the standard of care for helping to control increased uric acid levels caused by TLS.

Study Groups and Drug Administration:

Each cycle will last about 3 weeks.

If you are found to be eligible to take part in this study, you will receive rasburicase by vein over about 30 minutes on Day 1 of Cycle 1 (about 4 hours before you begin receiving chemotherapy). If the doctor thinks it is needed, you may also receive the drug on Days 2-5 of Cycle 1.

For Cycle 2, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups.

There is an equal chance of being assigned to either group:

• If you are in Group A, you will receive rasburicase on Day 1 of Cycle 2. If the doctor thinks it is needed, you may also receive the drug on Days 2-5 of Cycle 2.

• If you are in Group B, you will receive allopurinol by vein over 30 minutes each day on Days 1-5 of Cycle 2.

Group B Participants: If your uric acid blood levels continue to increase in Cycle 2 and you show symptoms of tumor lysis syndrome, you may receive rasburicase as a single dose. If the doctor thinks it is needed, you may also receive 1 or more additional dose(s).

Study Visits:

On Day 1 of Cycle 1:

• Blood (about 1 teaspoon) will be drawn to check uric acid levels before and 4 hours after you receive rasburicase.

• Blood (about 2 tablespoons) will be drawn for routine tests.

• Blood (about 1 teaspoon) will be drawn for antibody testing. Antibodies are proteins made by the body that the immune system uses to help prevent disease.

On Days 2-5 of Cycle 1:

• Blood (about 1 teaspoon) will be drawn to check uric acid levels.

• Blood (about 2 tablespoon) will be drawn for routine tests.

At the end of both cycles, blood (about 1 teaspoon) will be drawn for antibody testing.

Length of Study:

You will receive drugs on this study for up to 2 cycles. You will be taken off study if intolerable side effects occur.

Your participation in the study will be over after the follow-up visit.

Follow-Up:

Three (3) months after the end of Cycle 2, blood (about 1 teaspoon) will be drawn for antibody testing.

This is an investigational study. Allopurinol is commercially available and FDA approved to treat TLS. Rasburicase is commercially available and FDA approved for treating TLS for 1 cycle in patients with leukemia, lymphoma, and solid tumor cancers who are receiving anti-cancer therapy. It is investigational to give rasburicase for 2 cycles.

Up to 55 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 2 Study to Evaluate the Efficacy of Rasburicase in Patients at Risk for TLS During Two Cycles of Chemotherapy
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rasburicase Alone Rasburicase by vein on Day 1 (0.15 mg/kg or a flat dose of 3 mg) as a single dose, plus as needed dosing (until day 5), during cycle 1 (21 day cycle).	Drug: Rasburicase; Cycle 1: 3 mg/kg by vein on Day 1, plus as needed dosing (until day 5), during Cycle 1. Cycle 2 Arm A: 0.15 mg/kg by vein on Day 1 of Cycle 2, plus as needed dosing (until day 5), during Cycle 2.
Experimental: Arm A (Rasburicase) Participants randomized to Rasburicase (0.15 mg/kg) by vein on day 1 plus as needed dosing (until day 5) during Cycle 2.	Drug: Rasburicase; Cycle 1: 3 mg/kg by vein on Day 1, plus as needed dosing (until day 5), during Cycle 1. Cycle 2 Arm A: 0.15 mg/kg by vein on Day 1 of Cycle 2, plus as needed dosing (until day 5), during Cycle 2.
Experimental: Arm B (Allopurinol) Participants randomized to Allopurinol (300 mg/day) by vein each day on Days 1-5 of Cycle 2.	Drug: Allopurinol; Arm B: 300 mg/day by vein, as standard of care, over 30 minutes each day on days 1-5 of cycle 2 in 21 day cycle.; Other Names: Loprin Zurinol Zyloprim

Outcome Measures

Primary Outcome Measures

1. Number of Participants (Incidence) of LTLS (Laboratory Tumor Lysis Syndrome) [Up to two 3-week cycles, 6 weeks]

   Number of participants (incidence) of LTLS in the two arms, as defined by the Cairo-Bishop criteria , during cycle 2. Cairo-Bishop criteria: Uric acid x ≥ 476 μmol/l or 25% increase from baseline Potassium x ≥ 6·0 mmol/l or 25% increase from baseline Phosphorous x ≥ 2·1 mmol/l (children), x ≥1·45 mmol/l (adults) or 25% increase from baseline Calcium x ≤ 1·75 mmol/l or 25% decrease from baseline Laboratory tumour lysis syndrome (LTLS) is defined as either a 25% change or level above or below normal, as defined above, for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3d before or 7d after the initiation of chemotherapy.

2. Number of Cycle 2 Participants Normalizing Uric Acid Levels (UAL) Within 24 Hours of Treatment [Up to 24 hours of cycle 2 dose delivery]

   Number of participants with normalized UAL as determined by a uric acid blood test at either 24 hours. A uric acid blood test, also known as a serum uric acid measurement, determines how much uric acid is present in the blood where normal levels are 2.4-6.0 mg/dL (female) and 3.4-7.0 mg/dL (male).

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients that are high risk for TLS or potential/intermediate risk for TLS as described below: (a) High risk: Hyperuricemia of malignancy (Uric acid levels >7.5); or diagnosis of very aggressive lymphoma/leukemia based on Revised European-American Lymphoma (REAL) classification; acute myeloid leukemia, CML in blast crisis; high grade myelodysplastic syndrome only if they have >10% bone marrow blast involvement and given aggressive treatment similar to acute myeloid leukemia (AML). (b) Potential risk: Diagnosis of aggressive lymphoma/leukemia based on (REAL) classification. Plus one or more of the following criteria: lactate dehydrogenase (LDH) >/= 2 x upper limit of normal (UNL); Stage III-IV disease; Stage I-II disease with at least 1 lymph node/tumor > 5 cm in diameter. For patients with potential/intermediate risk for TLS- Only those planned to receive alternating regimens (or non-standard regimens) in 2 cycles (example; R-Hyper-central venous access device (CVAD) alternating with MTX/ARA-C) will be eligible.

2. Eastern Cooperative Oncology Group (ECOG) performance status 0-3.

3. Negative pregnancy test (females of child bearing potential) within </= 1 week of rasburicase dose and use of efficient contraceptive method (both males and females). Pregnancy test may be performed on serum (HCG) or urine (HCG).

4. Signed written informed consent approved by the Institutional Review Board obtained prior to study entry.

Exclusion Criteria:

1. Prior H/O severe allergy or asthma requiring active treatment.

2. Patients with mantle cell lymphoma (MCL) with stage 1 or 2 disease.

3. Patient receiving any investigational drug for hyperuricemia within 30 days of planned first treatment with rasburicase.

4. Pregnancy or lactation.

5. Known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

6. Known history of hemolysis and/or methemoglobinemia.

7. Previous therapy with urate oxidase.

8. Conditions unsuitable for participation in the trial in the Investigator's opinion.

9. Unwillingness to comply with the requirements of the protocol.

10. Use of allopurinol within 72 hours of the study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Sanofi

Investigators

• Principal Investigator: Saroj Vadhan-Raj, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01200485
• Other Study ID Numbers: 2010-0284; NCI-2012-01889
• First Posted: Sep 13, 2010
• Last Update Posted: Jan 31, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by M.D. Anderson Cancer Center: Supportive Care; Recombinant urate oxidase; Chemotherapy; Tumor Lysis Syndrome (TLS); Hematologic malignancies; Acute myeloid leukemia
• Additional relevant MeSH terms: Tumor Lysis Syndrome; Allopurinol; Rasburicase

Study Results

Participant Flow

Recruitment Details	Recruitment Period: April 25, 2011 to September 10, 2015. All recruitment done at The University of Texas MD Anderson Cancer Center.
Pre-assignment Detail	Cycle 2 is the study cycle; of the 55 participants enrolled on study, 52 were treated in cycle 1 (rasburicase alone), and only 46 were randomized onto the two arms in the study cycle (cycle 2, Arm A: Rasburicase; Arm B: Allopurinol).

Arm/Group Title	Cycle 1: Rasburicase Alone	Cycle 2, Arm A: Rasburicase	Cycle 2, Arm B: Allopurinol
Arm/Group Description	Rasburicase by vein on Day 1 (0.15 mg/kg or a flat dose of 3 mg) as a single dose, plus as needed dosing (until day 5), during cycle 1 (21 day cycle).	Rasburicase (0.15 mg/kg) by vein on day 1 plus as needed dosing (until day 5) during Cycle 2.	Allopurinol (300 mg/day) each day on Days 1-5 of Cycle 2.
Period Title: Cycle 1: Rasburicase Alone Delivery
STARTED	55	0	0
COMPLETED	52	0	0
NOT COMPLETED	3	0	0
Period Title: Cycle 1: Rasburicase Alone Delivery
STARTED	0	21	25
COMPLETED	0	21	25
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Rasburicase Alone
Arm/Group Description	Rasburicase by vein on Day 1 (0.15 mg/kg or a flat dose of 3 mg) as a single dose, plus as needed dosing (until day 5), during cycle 1
Overall Participants	55
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Age, Customized (years) [Median (Full Range) ]
Cycle 2, Arm A	52
Cycle 2, Arm B	56
Sex: Female, Male (Count of Participants)
Female	15 27.3%
Male	40 72.7%
Female	5 9.1%
Male	16 29.1%
Female	8 14.5%
Male	17 30.9%
Region of Enrollment (participants) [Number]
United States	55 100%
Eastern Cooperative Oncology Group (ECOG) PS, Cycle 1 (participants) [Number]
<2	53 96.4%
>/=2	2 3.6%
ECOG PS, Cycle 2 (Count of Participants)
<2	20 36.4%
>/=2	1 1.8%
<2	24 43.6%
>/=2	1 1.8%
Tumor Lysis Syndrome (TLS) Risk (Count of Participants)
High	22 40%
Potential	30 54.5%
Not evaluable	3 5.5%
Baseline Plasma Uric Acid (PUA) (Count of Participants)
<7.1 mg/dL	16 29.1%
>/=7.1 mg/dL	4 7.3%
Not evaluated	1 1.8%
<7.1 mg/dL	22 40%
>/=7.1 mg/dL	3 5.5%
Not evaluated	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants (Incidence) of LTLS (Laboratory Tumor Lysis Syndrome)
Description	Number of participants (incidence) of LTLS in the two arms, as defined by the Cairo-Bishop criteria , during cycle 2. Cairo-Bishop criteria: Uric acid x ≥ 476 μmol/l or 25% increase from baseline Potassium x ≥ 6·0 mmol/l or 25% increase from baseline Phosphorous x ≥ 2·1 mmol/l (children), x ≥1·45 mmol/l (adults) or 25% increase from baseline Calcium x ≤ 1·75 mmol/l or 25% decrease from baseline Laboratory tumour lysis syndrome (LTLS) is defined as either a 25% change or level above or below normal, as defined above, for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3d before or 7d after the initiation of chemotherapy.
Time Frame	Up to two 3-week cycles, 6 weeks

Outcome Measure Data

Analysis Population Description

All 46 participants treated in randomized cycle 2 of study were included in analysis.

Arm/Group Title	Arm A (Rasburicase)	Arm B (Allopurinol)
Arm/Group Description	Rasburicase (0.15 mg/kg) by vein on day 1 plus as needed dosing (until day 5) during Cycle 2.	Allopurinol (300 mg/day) each day on Days 1-5 of Cycle 2.
Measure Participants	21	25
Count of Participants [Participants]	1 1.8%	1 NaN

2. Primary Outcome

Title	Number of Cycle 2 Participants Normalizing Uric Acid Levels (UAL) Within 24 Hours of Treatment
Description	Number of participants with normalized UAL as determined by a uric acid blood test at either 24 hours. A uric acid blood test, also known as a serum uric acid measurement, determines how much uric acid is present in the blood where normal levels are 2.4-6.0 mg/dL (female) and 3.4-7.0 mg/dL (male).
Time Frame	Up to 24 hours of cycle 2 dose delivery

Outcome Measure Data

Analysis Population Description

One participant in Arm A missed one UA level assessment.

Arm/Group Title	Arm A (Rasburicase)	Arm B (Allopurinol)
Arm/Group Description	Rasburicase (0.15 mg/kg) by vein on day 1 plus as needed dosing (until day 5) during Cycle 2.	Allopurinol (300 mg/day) each day on Days 1-5 of Cycle 2.
Measure Participants	21	25
Count of Participants [Participants]	20 36.4%	25 NaN

Adverse Events

Time Frame	Adverse events were captured before and after each cycle, up to 30 days from day 1 of the study drug and clinical assessment
Arm/Group Title	Cycle 1: Rasburicase Alone		Cycle 2: Arm A (Rasburicase)		Cycle 2: Arm B (Allopurinol)
Arm/Group Description	Rasburicase by vein on Day 1 (0.15 mg/kg or a flat dose of 3 mg) as a single dose, plus as needed dosing (until day 5), during cycle 1 (21 day cycle).		Rasburicase (0.15 mg/kg) by vein on day 1 plus as needed dosing (until day 5) during Cycle 2.		Allopurinol (300 mg/day) each day on Days 1-5 of Cycle 2.
All Cause Mortality
	Cycle 1: Rasburicase Alone		Cycle 2: Arm A (Rasburicase)		Cycle 2: Arm B (Allopurinol)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		1/21 (4.8%)		1/25 (4%)
Serious Adverse Events
	Cycle 1: Rasburicase Alone		Cycle 2: Arm A (Rasburicase)		Cycle 2: Arm B (Allopurinol)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/52 (5.8%)		1/21 (4.8%)		1/25 (4%)
Blood and lymphatic system disorders
Methemoglobinemia	1/52 (1.9%)	1	0/21 (0%)	1	0/25 (0%)	1
General disorders
Death	0/52 (0%)	0	1/21 (4.8%)	1	1/25 (4%)	1
Renal and urinary disorders
Acute renal failure	2/52 (3.8%)		0/21 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Cycle 1: Rasburicase Alone		Cycle 2: Arm A (Rasburicase)		Cycle 2: Arm B (Allopurinol)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/52 (73.1%)		12/21 (57.1%)		17/25 (68%)
Gastrointestinal disorders
Constipation	23/52 (44.2%)		4/21 (19%)	4	9/25 (36%)	9
General disorders
Fatigue	21/52 (40.4%)		9/21 (42.9%)	9	8/25 (32%)	8
Investigations
Blood bilirubin increased	6/52 (11.5%)		1/21 (4.8%)	1	4/25 (16%)	4
Nervous system disorders
Headache	10/52 (19.2%)		4/21 (19%)	4	10/25 (40%)	10
Respiratory, thoracic and mediastinal disorders
Dyspnea	7/52 (13.5%)		1/21 (4.8%)	1	4/25 (16%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.