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

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

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.

Study Overview

• Status: Terminated
• Conditions: Tumor Lysis Syndrome
• Intervention / Treatment: Drug: Febuxostat

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria, 1527
    • University Hospital Tsaritsa Yoanna
• Hungary
  • Budapest, Hungary, 1085
    • Semmelweis Egyetem
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem (paediatric)
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont
• Italy
  • Bologna, Italy, 40138
    • Policlinico S. Orsola Malpighi
  • Firenze, Italy, 50139
    • Azienda Ospedaliero Universitaria Meyer
  • Firenze, Italy, 50134
    • A.O.U.C. Azienda Ospedaliero - Universitaria Careggi
  • Genova, Italy, 16147
    • Istituto G Gaslini Ospedale Pediatrico IRCCS
  • Pisa, Italy, 56126
    • Azienda Ospedaliero-Universitaria Pisana
  • Rome, Italy, 00165
    • IRCCS Ospedale Pediatrico Bambino Gesu
  • Torino, Italy, 10126
    • Ospedale Infantile Regina Margherita
  • Verona, Italy, 37126
    • Azienda Ospedaliera Universitaria Integrata Di Verona
  • Pordenone
    • Aviano, Pordenone, Italy, 33081
      • SOC Oncologia Medica A - Centro di Riferimento Oncologico
• Spain
  • Caceres, Spain, 10002
    • Hospital de San Pedro de Alcantara
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Valencia, Spain, 46026
    • Hospital Universitari I Politecnic La Fe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

male and female children of 6 to less than 12 years of age, adolescents of 12 to less than 18 years of age and adults from 18 years:

• scheduled for first cytotoxic chemotherapy cycle because of hematologic malignancies
• and at intermediate or high risk of TLS
• and with no access to rasburicase

Exclusion Criteria:

• patients with contraindications as per febuxostat summary of product characteristics
• patients with severe renal insufficiency
• patients with severe hepatic insufficiency
• patients with diagnosis of Laboratory TLS (LTLS) or Clinical TLS (CTLS)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Febuxostat film-coated tablets 2x20 mg/QD for 7-9 days	Drug: Febuxostat; Intervention is orally administered to patients in this arm.
Experimental: Cohort 2; Febuxostat film-coated tablets 3x20 mg/QD for 7-9 days	Drug: Febuxostat; Intervention is orally administered to patients in this arm.
Experimental: Cohort 3; Febuxostat film-coated tablets 1x80 mg/QD for 7-9 days (Adenuric® 80 mg)	Drug: Febuxostat; Intervention is orally administered to patients in this arm.
Experimental: Cohort 4; Febuxostat film-coated tablets 1x120 mg/QD for 7-9 days (Adenuric® 120 mg)	Drug: Febuxostat; Intervention is orally administered to patients in this arm.
Active Comparator: Adults; Febuxostat film-coated tablets 120 mg/QD for 7-9 days (Adenuric® 120 mg)	Drug: Febuxostat; Intervention is orally administered to patients in this arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/F)	Apparent clearance of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)	7 days
PK Parameter: Apparent Volume of Distribution (Vd/F)	Apparent volume of distribution of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)	7 days
PK Parameter: Absorption Rate Constant (Ka)	Absorption rate constant of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)	7 days
PK Parameter: Area Under Curve (AUC)	AUC of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)	7 days
PK Parameter: Maximum Plasma Concentration (Cmax)	Maximum plasma concentration of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)	7 days
PK Parameter: Tmax	Time to Cmax from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic (PD) Parameter: Area Under the Curve of Serum Uric Acid (sUA)	Area under the curve of sUA from baseline (Visit 1, Day 1) to the Evaluation Visit (Visit 8, Day 8) (AUC sUA 1-8)	8 days
Assessment of Laboratory Tumor Lysis Syndrome (LTLS)	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.	7 days
Assessment of Clinical Tumor Lysis Syndrome (CTLS)	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.	7 days
Assessment of Treatment Emergent Signs and Symptoms (TESS)	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.	Estimated maximum time frame: 27 days
Assessment of Participants Affected by Treatment Emergent Signs and Symptoms (TESS)	Number of participants affected by TESS from Screening Visit to End of Study Visit.	Estimated maximum time frame: 27 days
Performance Status (PS) Evaluation	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).	Estimated maximum time frame: 27 days

Collaborators and Investigators

• Sponsor: Menarini Group
• Investigators: Study Chair: Franco Locatelli, Prof, MD, IRCCS Ospedale Pediatrico Bambino Gesù, Piazza Sant'Onofrio, 4, 00165 Rome, IT

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2017
• Primary Completion (Actual): July 25, 2018
• Study Completion (Actual): July 25, 2018

Study Registration Dates

• First Submitted: May 29, 2018
• First Submitted That Met QC Criteria: July 19, 2018
• First Posted (Actual): July 30, 2018

Study Record Updates

• Last Update Posted (Actual): June 3, 2021
• Last Update Submitted That Met QC Criteria: May 10, 2021
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Hematological Malignancies; TLS; FLO-02
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Syndrome; Tumor Lysis Syndrome; Antirheumatic Agents; Gout Suppressants; Febuxostat
• Other Study ID Numbers: FLO-02; 2016-001445-61 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No