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

Primary Purpose

Tumor Lysis Syndrome

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Febuxostat
Sponsored by
Menarini Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Tumor Lysis Syndrome focused on measuring TLS, FLO-02, Hematological Malignancies

Eligibility Criteria

6 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • University Hospital Tsaritsa Yoanna
  • Semmelweis Egyetem (paediatric)
  • Semmelweis Egyetem
  • Debreceni Egyetem Klinikai Központ
  • SOC Oncologia Medica A - Centro di Riferimento Oncologico
  • Policlinico S. Orsola Malpighi
  • A.O.U.C. Azienda Ospedaliero - Universitaria Careggi
  • Azienda Ospedaliero Universitaria Meyer
  • Istituto G Gaslini Ospedale Pediatrico IRCCS
  • Azienda Ospedaliero-Universitaria Pisana
  • IRCCS Ospedale Pediatrico Bambino Gesù
  • Ospedale Infantile Regina Margherita
  • Azienda Ospedaliera Universitaria Integrata di Verona
  • Hospital de San Pedro de Alcantara
  • Hospital General Universitario Gregorio Maranon
  • Hospital Universitario La Paz
  • Hospital Universitari i Politècnic La Fe

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Active Comparator

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Adults

Arm Description

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)

Outcomes

Primary Outcome Measures

Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/F)
Apparent clearance of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
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)
PK Parameter: Absorption Rate Constant (Ka)
Absorption rate constant of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
PK Parameter: Area Under Curve (AUC)
AUC of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
PK Parameter: Maximum Plasma Concentration (Cmax)
Maximum plasma concentration of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
PK Parameter: Tmax
Time to Cmax from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)

Secondary Outcome Measures

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)
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.
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.
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.
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.
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).

Full Information

First Posted
May 29, 2018
Last Updated
May 10, 2021
Sponsor
Menarini Group
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1. Study Identification

Unique Protocol Identification Number
NCT03605212
Brief Title
Febuxostat for Tumor Lysis Syndrome Prevention in Hematological Malignancies of Paediatric Patients and Adults
Acronym
FLORET
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Terminated
Why Stopped
The study was stopped as per EMA waiver granted on 20July2018.
Study Start Date
February 27, 2017 (Actual)
Primary Completion Date
July 25, 2018 (Actual)
Study Completion Date
July 25, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Menarini Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tumor Lysis Syndrome
Keywords
TLS, FLO-02, Hematological Malignancies

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Febuxostat film-coated tablets 2x20 mg/QD for 7-9 days
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Febuxostat film-coated tablets 3x20 mg/QD for 7-9 days
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
Febuxostat film-coated tablets 1x80 mg/QD for 7-9 days (Adenuric® 80 mg)
Arm Title
Cohort 4
Arm Type
Experimental
Arm Description
Febuxostat film-coated tablets 1x120 mg/QD for 7-9 days (Adenuric® 120 mg)
Arm Title
Adults
Arm Type
Active Comparator
Arm Description
Febuxostat film-coated tablets 120 mg/QD for 7-9 days (Adenuric® 120 mg)
Intervention Type
Drug
Intervention Name(s)
Febuxostat
Intervention Description
Intervention is orally administered to patients in this arm.
Primary Outcome Measure Information:
Title
Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/F)
Description
Apparent clearance of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time Frame
7 days
Title
PK Parameter: Apparent Volume of Distribution (Vd/F)
Description
Apparent volume of distribution of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time Frame
7 days
Title
PK Parameter: Absorption Rate Constant (Ka)
Description
Absorption rate constant of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time Frame
7 days
Title
PK Parameter: Area Under Curve (AUC)
Description
AUC of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time Frame
7 days
Title
PK Parameter: Maximum Plasma Concentration (Cmax)
Description
Maximum plasma concentration of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time Frame
7 days
Title
PK Parameter: Tmax
Description
Time to Cmax from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time Frame
7 days
Secondary Outcome Measure Information:
Title
Pharmacodynamic (PD) Parameter: Area Under the Curve of Serum Uric Acid (sUA)
Description
Area under the curve of sUA from baseline (Visit 1, Day 1) to the Evaluation Visit (Visit 8, Day 8) (AUC sUA 1-8)
Time Frame
8 days
Title
Assessment of Laboratory Tumor Lysis Syndrome (LTLS)
Description
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.
Time Frame
7 days
Title
Assessment of Clinical Tumor Lysis Syndrome (CTLS)
Description
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.
Time Frame
7 days
Title
Assessment of Treatment Emergent Signs and Symptoms (TESS)
Description
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.
Time Frame
Estimated maximum time frame: 27 days
Title
Assessment of Participants Affected by Treatment Emergent Signs and Symptoms (TESS)
Description
Number of participants affected by TESS from Screening Visit to End of Study Visit.
Time Frame
Estimated maximum time frame: 27 days
Title
Performance Status (PS) Evaluation
Description
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).
Time Frame
Estimated maximum time frame: 27 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Franco Locatelli, Prof, MD
Organizational Affiliation
IRCCS Ospedale Pediatrico Bambino Gesù, Piazza Sant'Onofrio, 4, 00165 Rome, IT
Official's Role
Study Chair
Facility Information:
Facility Name
University Hospital Tsaritsa Yoanna
City
Sofia
ZIP/Postal Code
1527
Country
Bulgaria
Facility Name
Semmelweis Egyetem (paediatric)
City
Budapest
ZIP/Postal Code
1083
Country
Hungary
Facility Name
Semmelweis Egyetem
City
Budapest
ZIP/Postal Code
1085
Country
Hungary
Facility Name
Debreceni Egyetem Klinikai Központ
City
Debrecen
ZIP/Postal Code
4032
Country
Hungary
Facility Name
SOC Oncologia Medica A - Centro di Riferimento Oncologico
City
Aviano
State/Province
Pordenone
ZIP/Postal Code
33081
Country
Italy
Facility Name
Policlinico S. Orsola Malpighi
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
A.O.U.C. Azienda Ospedaliero - Universitaria Careggi
City
Firenze
ZIP/Postal Code
50134
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria Meyer
City
Firenze
ZIP/Postal Code
50139
Country
Italy
Facility Name
Istituto G Gaslini Ospedale Pediatrico IRCCS
City
Genova
ZIP/Postal Code
16147
Country
Italy
Facility Name
Azienda Ospedaliero-Universitaria Pisana
City
Pisa
ZIP/Postal Code
56126
Country
Italy
Facility Name
IRCCS Ospedale Pediatrico Bambino Gesù
City
Rome
ZIP/Postal Code
00165
Country
Italy
Facility Name
Ospedale Infantile Regina Margherita
City
Torino
ZIP/Postal Code
10126
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Integrata di Verona
City
Verona
ZIP/Postal Code
37126
Country
Italy
Facility Name
Hospital de San Pedro de Alcantara
City
Caceres
ZIP/Postal Code
10002
Country
Spain
Facility Name
Hospital General Universitario Gregorio Maranon
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Hospital Universitari i Politècnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain

12. IPD Sharing Statement

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

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