Tumor Lysis Syndrome
Conditions
Keywords
TLS, FLO-02, Hematological Malignancies
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.
Interventions
DRUGFebuxostat
Intervention is orally administered to patients in this arm.
Sponsors
Menarini Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter: Tmax | 7 days | Time to Cmax from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8) |
| PK Parameter: Area Under Curve (AUC) | 7 days | AUC of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8) |
| Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/F) | 7 days | Apparent clearance of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8) |
| PK Parameter: Apparent Volume of Distribution (Vd/F) | 7 days | Apparent volume of distribution of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8) |
| PK Parameter: Absorption Rate Constant (Ka) | 7 days | Absorption rate constant of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8) |
| PK Parameter: Maximum Plasma Concentration (Cmax) | 7 days | Maximum plasma concentration of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic (PD) Parameter: Area Under the Curve of Serum Uric Acid (sUA) | 8 days | 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) | 7 days | 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) | 7 days | 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) | Estimated maximum time frame: 27 days | 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) | Estimated maximum time frame: 27 days | Number of participants affected by TESS from Screening Visit to End of Study Visit. |
| Performance Status (PS) Evaluation | Estimated maximum time frame: 27 days | 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). |
Countries
Bulgaria, Hungary, Italy, Spain
Participant flow
Recruitment details
The first patient was screened and enrolled on 27 Feb 2017. The last patient completed the study on 16 Jul 2018. The study was conducted at 17 sites in 4 European countries.
Pre-assignment details
A total of 31 patients was screened, of whom 30 were enrolled and 28 completed the study regularly. Two enrolled patients were withdrawn from study drug treatment.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Febuxostat film-coated tablets 2x20 mg/QD for 7-9 days
Febuxostat: Intervention is orally administered to patients in this arm. | 3 |
| Cohort 2 Febuxostat film-coated tablets 3x20 mg/QD for 7-9 days
Febuxostat: Intervention is orally administered to patients in this arm. | 0 |
| Cohort 3 Febuxostat film-coated tablets 1x80 mg/QD for 7-9 days (Adenuric® 80 mg)
Febuxostat: Intervention is orally administered to patients in this arm. | 3 |
| Cohort 4 Febuxostat film-coated tablets 1x120 mg/QD for 7-9 days (Adenuric® 120 mg)
Febuxostat: Intervention is orally administered to patients in this arm. | 0 |
| Adults Febuxostat film-coated tablets 1x120 mg/QD for 7-9 days (Adenuric® 120 mg)
Febuxostat: Intervention is orally administered to patients in this arm. | 24 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Treatment Period | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Treatment Period | Physician Decision | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Adults | Total | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 6 Participants | 3 Participants | 0 Participants | 3 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 10 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 14 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 60.21 years STANDARD_DEVIATION 15.376 | 50.30 years STANDARD_DEVIATION 24.419 | 7.33 years STANDARD_DEVIATION 1.528 | — | 14.00 years STANDARD_DEVIATION 1 | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 29 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 28 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Bulgaria | 0 participants | 0 participants | 0 participants | — | 0 participants | — |
| Region of Enrollment Hungary | 8 participants | 8 participants | 0 participants | — | 0 participants | — |
| Region of Enrollment Italy | 5 participants | 11 participants | 3 participants | — | 3 participants | — |
| Region of Enrollment Spain | 11 participants | 11 participants | 0 participants | — | 0 participants | — |
| Sex: Female, Male Female | 11 Participants | 14 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 16 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Weight | 75.60 kg STANDARD_DEVIATION 15.469 | 68.92 kg STANDARD_DEVIATION 21.369 | 26.13 kg STANDARD_DEVIATION 2.043 | — | 60.47 kg STANDARD_DEVIATION 19.747 | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 0 | 0 / 3 | 0 / 0 | 0 / 24 |
| other Total, other adverse events | 3 / 3 | 0 / 0 | 3 / 3 | 0 / 0 | 20 / 24 |
| serious Total, serious adverse events | 1 / 3 | 0 / 0 | 0 / 3 | 0 / 0 | 5 / 24 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/F)
Apparent clearance of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time frame: 7 days
Population: Data were not collected.
Primary
PK Parameter: Absorption Rate Constant (Ka)
Absorption rate constant of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time frame: 7 days
Population: Data were not collected.
Primary
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)
Time frame: 7 days
Population: Data were not collected.
Primary
PK Parameter: Area Under Curve (AUC)
AUC of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time frame: 7 days
Population: Data were not collected.
Primary
PK Parameter: Maximum Plasma Concentration (Cmax)
Maximum plasma concentration of febuxostat from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time frame: 7 days
Population: Data were not collected.
Primary
PK Parameter: Tmax
Time to Cmax from Visit 2 (Day 2) to Evaluation Visit (Visit 8, Day 8)
Time frame: 7 days
Population: Data were not collected.
Secondary
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.
Time frame: 7 days
Population: Data were not collected.
Secondary
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.
Time frame: 7 days
Population: Data were not collected.
Secondary
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.
Time frame: Estimated maximum time frame: 27 days
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Assessment of Participants Affected by Treatment Emergent Signs and Symptoms (TESS) | 3 participants |
| Cohort 3 | Assessment of Participants Affected by Treatment Emergent Signs and Symptoms (TESS) | 3 participants |
| Adults | Assessment of Participants Affected by Treatment Emergent Signs and Symptoms (TESS) | 20 participants |
Secondary
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.
Time frame: Estimated maximum time frame: 27 days
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | TESS | 50 Events |
| Cohort 1 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | TESS grade >/=3 | 11 Events |
| Cohort 1 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Serious TESS | 1 Events |
| Cohort 1 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS | 4 Events |
| Cohort 1 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS grade >/=3 | 2 Events |
| Cohort 1 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS/Drug Withdrawn | 2 Events |
| Cohort 3 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS/Drug Withdrawn | 0 Events |
| Cohort 3 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | TESS | 21 Events |
| Cohort 3 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS | 0 Events |
| Cohort 3 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS grade >/=3 | 0 Events |
| Cohort 3 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | TESS grade >/=3 | 2 Events |
| Cohort 3 | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Serious TESS | 0 Events |
| Adults | Assessment of Treatment Emergent Signs and Symptoms (TESS) | TESS grade >/=3 | 20 Events |
| Adults | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Serious TESS | 7 Events |
| Adults | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS/Drug Withdrawn | 0 Events |
| Adults | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS | 0 Events |
| Adults | Assessment of Treatment Emergent Signs and Symptoms (TESS) | TESS | 70 Events |
| Adults | Assessment of Treatment Emergent Signs and Symptoms (TESS) | Related TESS grade >/=3 | 0 Events |
Secondary
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).
Time frame: Estimated maximum time frame: 27 days
Population: Data were not collected.
Secondary
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)
Time frame: 8 days
Population: Data were not collected.