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Tumor Lysis Syndrome

Hematologic Diseases

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Antirheumatic Agents

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Febuxostat

Allopurinol

Antimetabolites

Enzyme Inhibitors

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Protective Agents

Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)

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)

Michele Spina, MD

Angela Capriati, MD, PhD

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

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.

Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies

Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies: a Randomized, Double Blind, Phase III Study Versus Allopurinol

Incidence, severity, seriousness and treatment-causality of TESS

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

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

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

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.

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

Menarini Group

Analysed for the Safety Population (all patients who received the study drug)

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

Age, Continuous

Sex: Female, Male

< or = 7.5 mg/dL

> 7.5 mg/dL

serum uric acid (sUA)

Intermediate

High

TLS risk

Acute leukemia

Chronic lymphocytic leukemia

Type of Hematologic Malignancy

Dr. Angela Capriati, Corporate Clinical Research Director

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

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.

Serum Uric Acid (sUA) Level Control

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

Preservation of Renal Function

Intention to Treat (ITT; no imputation applied

Treatment Responder Rate

Assessment of Laboratory Tumor Lysis Syndrome (LTLS)

Assessment of Clinical Tumor Lysis Syndrome (CTLS)

Treatment Emergent Signs or Symptoms (TESS)

Overall Study

Febuxostat film-coated tablets 2x20 mg/QD for 7-9 days

Febuxostat film-coated tablets 3x20 mg/QD for 7-9 days

Febuxostat film-coated tablets 1x80 mg/QD for 7-9 days (Adenuric® 80 mg)

Febuxostat film-coated tablets 1x120 mg/QD for 7-9 days (Adenuric® 120 mg)

Febuxostat film-coated tablets 120 mg/QD for 7-9 days (Adenuric® 120 mg)

Intervention is orally administered to patients in this arm.

Franco Locatelli, Prof, MD

The purpose of this study is to compare the exposure of febuxostat in pediatric patients (≥6\<18 years of age) and in adults suffering from hematological malignancies at intermediate to high risk of TLS and to compare the effect in terms of serum uric acid levels.

In the FLORET study it is planned to enroll 3 groups of patients in order to receive oral administration (film-coated tablets) of two different dose levels of febuxostat: children (from 6 to less than 12 years of age) will receive two different dose levels respectively; adolescents (from 12 to less than 18 years of age) will receive 80 and 120 mg/day respectively and adults (equal or major than 18 years of age) will receive 120 mg/day. The two dose levels for children and adolescents groups were to be sequentially administered, whereas the groups that will receive the first dose levels will simultaneously start the treatment at the study beginning. The individual treatment duration will be of 7 to 9 days, according to chemotherapy duration, as per Investigator's judgement.

Febuxostat for Tumor Lysis Syndrome Prevention in Hematological Malignancies of Paediatric Patients and Adults

Open Label, Multi-centre, Parallel Group Study to Compare the Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of Febuxostat Between Pediatric Patients (≥6<18 Years of Age) and Adults

Apparent clearance of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)

Apparent volume of distribution of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)

Absorption rate constant of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)

AUC of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)

Maximum plasma concentration of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)

Time to Cmax from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)

Area under the curve of sUA from baseline (Visit 1, Day 1) to the Evaluation Visit (Visit 8, Day 8) (AUC sUA 1-8)

Assessment of LTLS at Visit 1 (Day 1) and from Start of Chemotherapy (Visit 3, Day 3) to the Evaluation Visit (Visit 8, Day 8). LTLS is diagnosed if levels of 2 or more values of uric acid, potassium, phosphate or calcium are more than or less than normal at presentation or if they change by at least 25% from baseline.

Assessment of CTLS at Visit 1 (Day 1) and from Start of Chemotherapy (Visit 3, Day 3) to the Evaluation Visit (Visit 8, Day 8). CTLS is present when LTLS is accompanied by at least one of the following significant clinical complications: increased creatinine level ≥ 1.5 upper limit of normal, cardiac arrhythmia/sudden death or seizure.

Assessment of incidence, severity (through Mild/Moderate/Severe scale), seriousness and treatment-causality of TESS from Screening Visit to End of Study Visit. Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. An adverse event was considered as TESS if it occured for the first time or if it worsened in terms of seriousness or severity after first study drug intake.

Number of participants affected by TESS from Screening Visit to End of Study Visit.

Quality of life was to be assessed by PS evaluation from Screening Visit to End of Study Visit. The Karnofsky Performance Status (KPS) scale was to be used for patients aged 16 years and older; the Lansky Play Performance Status (LPS) scale was to be used for patients aged less than 16 years. Both scales range from scores of 0 to 100 points at intervals of 10 where 0 points represent the worst outcome (KPS: 0 = death; LPS: 0 = unresponsive) and 100 points the best (KPS: 100 = normal, no complaints, no evidence of disease; LPS: 100 = fully active).

Adverse Events were collected during Screening, i.e. after ICF signature until DAY 1, Visit 1 before first IMP intake and specifically Treatment Emergent Signs and Symptoms (TESSs) occurring from first IMP intake at Visit 1, DAY 1 until Visit 10, DAY 14.

Febuxostat film-coated tablets 2x20 mg/QD for 7-9 days

Febuxostat: Intervention is orally administered to patients in this arm.

Cohort 1

Febuxostat film-coated tablets 3x20 mg/QD for 7-9 days

Febuxostat: Intervention is orally administered to patients in this arm.

Cohort 2

Febuxostat film-coated tablets 1x80 mg/QD for 7-9 days (Adenuric® 80 mg)

Febuxostat: Intervention is orally administered to patients in this arm.

Cohort 3

Febuxostat film-coated tablets 1x120 mg/QD for 7-9 days (Adenuric® 120 mg)

Febuxostat: Intervention is orally administered to patients in this arm.

Cohort 4

Adults

Age, Categorical

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Hungary

Italy

Bulgaria

Spain

Region of Enrollment

Weight

Data for all outcome measures were not collected due to the paucity of data in the minor patient population and in agreement with EMA with the exceptions of the secondary outcome Assessment of Treatment Emergent Signs and Symptoms (TESS).

Angela Capriati, MD PhD - Corporate Director Clinical Sciences

Febuxostat film-coated tablets 120 mg/QD for 7-9 days (Adenuric® 120 mg)

Febuxostat: Intervention is orally administered to patients in this arm.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies	NCT01724528	Tumor Lysis Syn...	Febuxostat Allopurinol	18 Years -	Menarini Group
Febuxostat for Tumor Lysis Syndrome Prevention in Hematological Malignancies of Paediatric Patients and Adults	NCT03605212	Tumor Lysis Syn...	Febuxostat	6 Years -	Menarini Group
Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies	NCT01724528	Tumor Lysis Syn...	Febuxostat Allopurinol	18 Years -	Menarini Group

Spots Global Cancer Trial Database for febuxostat

Every month we try and update this database with for febuxostat cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for febuxostat

Every month we try and update this database with for febuxostat cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for febuxostat cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.