FLORENCE: Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies

• Sponsor: Menarini Group (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01724528
• Collaborator: (none)
• Enrollment: 346
• Arms: 2
• Duration (Months): 12

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether febuxostat is superior to allopurinol in the prevention of tumor lysis syndrome (TLS) in patients with hematological malignancies at intermediate or high risk of TLS (according to Cairo-Bishop classification) who undergo chemotherapy

Condition or Disease	Intervention/Treatment	Phase
Tumor Lysis Syndrome	Drug: Febuxostat; Drug: Allopurinol	Phase 3

Detailed Description

This study is designed as a randomised, double-blind, active-controlled, parallel-group study to be conducted in approximately 80 sites.

Approximately 340 male or female patients aged 18 or older suffering from hematologic malignancies (de novo patients or relapsing patients) at intermediate to high risk of TLS and scheduled for receiving the first cycle of cytotoxic chemotherapy, regardless of the line of treatment, will be randomized in this study. Eligible patients (as per screening visit) will be randomly allocated in a 1:1 ratio to Febuxostat or Allopurinol. The double-blind treatment period starts two days prior to the planned beginning of chemotherapy and continues for 7 to 9 consecutive days, according to Investigator judgment and on the basis of the actual duration of chemotherapy regimen administered to the patient. Along the study treatment, uric acid levels, creatinine levels, Laboratory TLS/Clinical TLS and Adverse Events represent the major clinical findings to be monitored on a daily basis. Overall the study encompasses 10 to 11 planned visits at site, including screening, randomisation, on treatment and final follow up visits.

Study Design

• Study Type: Interventional
• Actual Enrollment: 346 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies: a Randomized, Double Blind, Phase III Study Versus Allopurinol
• Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Febuxostat Febuxostat for 7-9 days	Drug: Febuxostat; Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion); Other Names: Adenuric
Active Comparator: Allopurinol Allopurinol for 7-9 days	Drug: Allopurinol; Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion); Other Names: Zyloric

Outcome Measures

Primary Outcome Measures

1. Serum Uric Acid (sUA) Level Control [8 days]

   Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8)

2. Preservation of Renal Function [8 days]

   Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8)

Secondary Outcome Measures

1. Treatment Responder Rate [6 days]

   Assessment of treatment responder rate, where treatment response is defined as the maintenance of sUA ≤ 7.5 mg/dL from Day 3 to Day 8

2. Assessment of Laboratory Tumor Lysis Syndrome (LTLS) [6 days]

   Assessment of LTLS, from Day 3 to Day 8. According to Cairo-Bishop definition LTLS is defined by the presence of 2 or more laboratory abnormalities including: a 25% increase or levels above normal for serum uric acid, potassium, and phosphate or a 25% decrease or levels below normal for calcium.

3. Assessment of Clinical Tumor Lysis Syndrome (CTLS) [6 days]

   Assessment of CTLS, from Day 3 to Day 8. According to Cairo-Bishop definition, CTLS is defined by the presence of LTLS in addition to 1 or more of the following significant clinical complications: renal insufficiency, cardiac arrhythmias, sudden death and seizures. The grade of CTLS is defined by the maximal grade of the clinical manifestation

Other Outcome Measures

1. Treatment Emergent Signs or Symptoms (TESS) [14 ± 2 days]

   Incidence, severity, seriousness and treatment-causality of TESS

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients scheduled for first cytotoxic chemotherapy cycle, regardless of the line of treatment, because of hematologic malignancies at intermediate or high risk of TLS (according to the TLS risk stratification, Cairo M et al, British Journal of Haematology, 2010)candidate to Allopurinol treatment or have no access to Rasburicase

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3

• Life expectancy > 1 month

Exclusion Criteria:

• Patients known to be hypersensitive to Febuxostat or Allopurinol or to any of the components of the formulations

• Patients with sUA levels ≥ 10 mg/dL at randomization

• Patients receiving Febuxostat, Allopurinol or any other urate lowering therapy (e.g. Rasburicase, probenecid) within 30 days prior to randomization

• Patients with severe renal and/or hepatic insufficiency

• Patients with diagnosis of LTLS or CTLS at randomization

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Menarini Group

Investigators

• Principal Investigator: Michele Spina, MD, Centro Riferimento Oncologico (CRO) National Cancer Institute-Aviano-Italy
• Study Director: Angela Capriati, MD, PhD, Menarini Ricerche S.p.A. - Florence-Italy

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Menarini Group
• ClinicalTrials.gov Identifier: NCT01724528
• Other Study ID Numbers: FLO-01; 2012-000776-42
• First Posted: Nov 9, 2012
• Last Update Posted: Nov 2, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Menarini Group: Febuxostat, Tumor lysis syndrome, leukemia, lymphoma
• Additional relevant MeSH terms: Hematologic Neoplasms; Tumor Lysis Syndrome; Syndrome; Allopurinol; Febuxostat

Study Results

Participant Flow

Recruitment Details	First patient in (screening) 01 Oct 2012, last patient out 11 Oct 2013. At 79 sites across 11 European countries (Croatia, Czech Republic, Germany, Hungary, Italy, Poland, Romania, Russia, Serbia, Spain and Ukraine) and Brazil
Pre-assignment Detail	Subjects complying with inclusion/exclusion criteria were to be randomised to receive (blinded) standard, low or high dose of study treatment as per investigator's assessment (mainly based on renal function). Randomization was balanced by TLS risk and serum uric acid levels (≤ or > 7.5 mg/dL)

Arm/Group Title	Febuxostat	Allopurinol
Arm/Group Description	Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)	Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)
Period Title: Overall Study
STARTED	173	173
COMPLETED	169	170
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	Febuxostat	Allopurinol	Total
Arm/Group Description	Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)	Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)	Total of all reporting groups
Overall Participants	173	173	346
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.5 (14.26)	58.3 (13.26)	58.4 (13.75)
Sex: Female, Male (Count of Participants)
Female	65 37.6%	67 38.7%	132 38.2%
Male	108 62.4%	106 61.3%	214 61.8%
serum uric acid (sUA) (participants) [Number]
< or = 7.5 mg/dL	151 87.3%	152 87.9%	303 87.6%
> 7.5 mg/dL	22 12.7%	21 12.1%	43 12.4%
TLS risk (participants) [Number]
Intermediate	143 82.7%	141 81.5%	284 82.1%
High	30 17.3%	32 18.5%	62 17.9%
Type of Hematologic Malignancy (participants) [Number]
Acute leukemia	34 19.7%	25 14.5%	59 17.1%
Chronic lymphocytic leukemia	80 46.2%	94 54.3%	174 50.3%
Lymphoma	59 34.1%	54 31.2%	113 32.7%

Outcome Measures

1. Primary Outcome

Title	Serum Uric Acid (sUA) Level Control
Description	Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8)
Time Frame	8 days

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT), defined as all randomized patients. Sample size calculation: at least an absolute reduction of 100 mg x h/dL for the AUCsUA1-8 in favour of febuxostat; 340 patients were sufficient to achieve approximately 80% power. Imputation method: last observation carried forward (LOCF); missing baseline values were not replaced.

Arm/Group Title	Febuxostat	Allopurinol
Arm/Group Description	Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)	Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)
Measure Participants	172	172
Mean (Standard Deviation) [mg x hour/dL]	514.0 (225.71)	708.0 (234.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments	Treatment, TLS risk (intermediate/high) and sUA level at baseline (≤ 7.5 mg/dL and > 7.5 mg/dL) were inserted in the ANCOVA model as covariates
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares means difference
	Estimated Value	-196.794
	Confidence Interval	(2-Sided) 95%; -238.600 to -154.988
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Preservation of Renal Function
Description	Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8)
Time Frame	8 days

Outcome Measure Data

Analysis Population Description

ITT. Sample size calculation: no change in mean serum creatinine level from baseline to the end of treatment for febuxostat group while allopurinol has a increase of 13%; 340 patients were sufficient to achieve approximately 80% power. Imputation method: LOCF; missing baseline values were not replaced

Arm/Group Title	Febuxostat	Allopurinol
Arm/Group Description	Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)	Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)
Measure Participants	173	171
Mean (Standard Deviation) [change %]	-0.83 (26.977)	-4.92 (16.695)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments	Treatment, TLS risk (intermediate/high) and sUA level at baseline (≤ 7.5 mg/dL and > 7.5 mg/dL) were inserted in the ANCOVA model as covariates
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0903
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares means difference
	Estimated Value	4.0970
	Confidence Interval	(2-Sided) 95%; -0.6467 to 8.8406
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Treatment Responder Rate
Description	Assessment of treatment responder rate, where treatment response is defined as the maintenance of sUA ≤ 7.5 mg/dL from Day 3 to Day 8
Time Frame	6 days

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT; no imputation applied

Arm/Group Title	Febuxostat	Allopurinol
Arm/Group Description	Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)	Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)
Measure Participants	173	173
Number [% of patients who fail to respond]	1.7	4.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1993
	Comments
	Method	Wilson's confidence interval
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.0231
	Confidence Interval	(2-Sided) 95%; -0.0153 to 0.0654
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Assessment of Laboratory Tumor Lysis Syndrome (LTLS)
Description	Assessment of LTLS, from Day 3 to Day 8. According to Cairo-Bishop definition LTLS is defined by the presence of 2 or more laboratory abnormalities including: a 25% increase or levels above normal for serum uric acid, potassium, and phosphate or a 25% decrease or levels below normal for calcium.
Time Frame	6 days

Outcome Measure Data

Analysis Population Description

ITT; no imputation applied

Arm/Group Title	Febuxostat	Allopurinol
Arm/Group Description	Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)	Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)
Measure Participants	173	173
Number [% of patients with LTLS occurrence]	8.1	9.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8488
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Relative risk
	Estimated Value	0.875
	Confidence Interval	(2-Sided) 95%; 0.4408 to 1.7369
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Assessment of Clinical Tumor Lysis Syndrome (CTLS)
Description	Assessment of CTLS, from Day 3 to Day 8. According to Cairo-Bishop definition, CTLS is defined by the presence of LTLS in addition to 1 or more of the following significant clinical complications: renal insufficiency, cardiac arrhythmias, sudden death and seizures. The grade of CTLS is defined by the maximal grade of the clinical manifestation
Time Frame	6 days

Outcome Measure Data

Analysis Population Description

ITT; no imputation applied

Arm/Group Title	Febuxostat	Allopurinol
Arm/Group Description	Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)	Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)
Measure Participants	173	173
Number [% of patients with CTLS occurrence]	1.7	1.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Allopurinol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Relative risk
	Estimated Value	0.994
	Confidence Interval	(2-Sided) 95%; 0.9691 to 1.0199
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Treatment Emergent Signs or Symptoms (TESS)
Description	Incidence, severity, seriousness and treatment-causality of TESS
Time Frame	14 ± 2 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	14 ± 2 days
Adverse Event Reporting Description	Analysed for the Safety Population (all patients who received the study drug)
Arm/Group Title	Febuxostat		Allopurinol
Arm/Group Description	Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)		Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)
All Cause Mortality
	Febuxostat		Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Febuxostat		Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/173 (12.1%)		6/173 (3.5%)
Blood and lymphatic system disorders
Anaemia	1/173 (0.6%)	1	0/173 (0%)	0
Febrile neutropenia	3/173 (1.7%)	3	1/173 (0.6%)	1
Leukopenia	2/173 (1.2%)	2	0/173 (0%)	0
Neutropenia	1/173 (0.6%)	1	1/173 (0.6%)	1
Thrombocytopenia	0/173 (0%)	0	1/173 (0.6%)	1
Cardiac disorders
Atrial Fibrillation	2/173 (1.2%)	2	0/173 (0%)	0
Cardiac failure acute	1/173 (0.6%)	1	0/173 (0%)	0
Myocardial ischaemia	1/173 (0.6%)	1	0/173 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/173 (0.6%)	1	0/173 (0%)	0
General disorders
Pyrexia	1/173 (0.6%)	1	0/173 (0%)	0
Infections and infestations
Bronchitis	1/173 (0.6%)	2	0/173 (0%)	0
Pneumonia	5/173 (2.9%)	5	2/173 (1.2%)	2
Sepsis	3/173 (1.7%)	3	0/173 (0%)	0
Septic shock	1/173 (0.6%)	1	0/173 (0%)	0
Investigations
Blood bilirubin increased	1/173 (0.6%)	1	0/173 (0%)	0
Platelet count decreased	1/173 (0.6%)	1	1/173 (0.6%)	1
White blood cell count decreased	1/173 (0.6%)	1	0/173 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	0/173 (0%)	0	1/173 (0.6%)	1
Hypovolaemia	1/173 (0.6%)	1	0/173 (0%)	0
Tumour lysis syndrome	1/173 (0.6%)	1	0/173 (0%)	0
Nervous system disorders
Cerebral ischaemia	1/173 (0.6%)	1	0/173 (0%)	0
Headache	2/173 (1.2%)	2	0/173 (0%)	0
Renal and urinary disorders
Haematuria	1/173 (0.6%)	1	0/173 (0%)	0
Renal failure	1/173 (0.6%)	1	0/173 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/173 (0.6%)	1	0/173 (0%)	0
Respiratory failure	1/173 (0.6%)	1	0/173 (0%)	0
Vascular disorders
Hypotension	0/173 (0%)	0	1/173 (0.6%)	1
Shock	1/173 (0.6%)	1	0/173 (0%)	0
Other (Not Including Serious) Adverse Events
	Febuxostat		Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	116/173 (67.1%)		112/173 (64.7%)
Blood and lymphatic system disorders
Anaemia	38/173 (22%)	48	25/173 (14.5%)	31
Leukopenia	25/173 (14.5%)	26	27/173 (15.6%)	27
Neutropenia	30/173 (17.3%)	32	40/173 (23.1%)	42
Thrombocytopenia	25/173 (14.5%)	28	19/173 (11%)	20
Gastrointestinal disorders
Constipation	14/173 (8.1%)	16	11/173 (6.4%)	12
Diarrhoea	16/173 (9.2%)	21	11/173 (6.4%)	13
Nausea	22/173 (12.7%)	25	21/173 (12.1%)	23
Vomiting	10/173 (5.8%)	11	12/173 (6.9%)	12
General disorders
Mucosal inflammation	11/173 (6.4%)	11	3/173 (1.7%)	3
Pyrexia	23/173 (13.3%)	25	18/173 (10.4%)	21
Investigations
Platelet count decreased	9/173 (5.2%)	9	6/173 (3.5%)	6
Metabolism and nutrition disorders
Hyperglycaemia	6/173 (3.5%)	7	9/173 (5.2%)	10
Hyperphosphataemia	9/173 (5.2%)	9	4/173 (2.3%)	4
Nervous system disorders
Headache	13/173 (7.5%)	14	5/173 (2.9%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.