Back to resultsEarly and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS
Primary Purpose
Myelodysplastic Syndromes
Status
Terminated
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Deferasirox
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring MDS
Eligibility Criteria
Inclusion Criteria:
- Diagnosis: Adult Myelodysplastic Syndrome (≥18 years).
- Revised IPSS: very low. low - intermediate
- Having received 5-20 packed red blood cell units
- Serum ferritin ≥300 ng/ml
- Transferrin saturation ≥ 60%
- Chelation naïve
- Capability to provide informed consent
Exclusion Criteria:
- Patients aged <18 years old
- Higher risk (revised IPSS) MDS (Intermediate 2, high)
- Cumulative transfusion story of > 20 packed red cell units
- Creatinine Clearance (CrCL): <60 ml/min. Patients with CrCl of 40-60ml/min will be included only individually if no other renal risk factors are present.
- Serum creatinine >2 x ULN at screening. If borderline serum creatinine will be measured within 7-10 days and the mean value will be used for eligibility criteria.
- Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-first void urine sample (or alternatively in two of three samples obtained for screening).
- ECOG performance status >2.
- Left ventricular ejection fraction < 50% by echocardiography
- A history of repeated hospitalization for congestive heart failure.
- Systemic diseases that would prevent study treatment (e.g. uncontrolled hypertension, cardiovascular, renal, hepatic, metabolic, etc.)
- Clinical or laboratory evidence of chronic Hepatitis B or Hepatitis C (definition of chronic hepatitis follows EASL 2017 criteria).
- History of HIV positive test result (ELISA or Western blot).
- Treatment with systemic investigational drug within 4 weeks or topical investigational drug within 7 days of study start.
- ALT or AST over 3 times superior to ULN at screening.
- ANC < 500/ microL
- Platelets transfusion dependency
- Total bilirubin over 1.5 times superior to ULN at screening (patients with Gilbert syndrome are allowed to enter the study)
- Diagnosis of Child score C liver cirrhosis.
- Patients participating in another clinical trial other than an observational registry study.
- Patients with a history of another malignancy within the past 3 years, with the exception of basal skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ.
- History of non-compliance to medical regimens, or patients who are considered potentially unreliable and/or not cooperative.
- Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug.
- Pregnant, intending-to-become pregnant, or breast-feeding patients.
- Women of potential maternity age who do not agree to practice effective contraceptive methods fo the entire study duration.
- History of drug or alcohol abuse within the 12 months prior to enrollment.
- Hypersensitivity to the active substance or to any of the excipients.
- Inability to provide a valid informed consent
Sites / Locations
- S.O.D. Ematologia Policlino Careggi
- Medicina Interna II Divisione di Ematologia, Ospedale S. Luigi Gonzaga
- Ematologia - Spedali Civili
- Ospedale Businco
- Ospedale San Martino
- Ospedale Niguarda
- Azienda Ospedaliera di Padova
- AO Bianchi Melacrino Morelli
- Ospedale S. Eugenio
- Istituto clinico Humanitas
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Deferasirox
Arm Description
patients will be assigned to a fixed dose of 3.5 mg/kg/day of DFX FCT.
Outcomes
Primary Outcome Measures
Change of hepatic iron
Change of hepatic iron from the baseline according to baseline hepatic iron level: For patients with baseline LIC ≤5 mg/g dry weight (dw) ± 1.5 mg/g dw. For patients with baseline LIC >5 mg/g dw ±20%
Secondary Outcome Measures
Definition of iron overload
The baseline iron status of MDS patients at the beginning of their transfusion story is today unknown. This study is the first unbiased and direct measurement of iron stress and oxidative stress in MDS patients at the beginning of the transfusion story.
Baseline iron status will be described by classical iron markers:
serum ferritin (ng/ml), transferritin saturation (%), liver and pancreas iron concentration by MRI (mg/g dry weight). Total body iron stores will be calculated (mg/kg) with the published formula (N Engl J Med 2000; 343:327-331).
Tissue reactive oxygen species will be measured in the patient's plasma as follows:
non-transferrin bound iron= micromoles/L, Labile Plasma Iron= micromoles/L. Oxidative stress will be measured by Malonildialdehyde (MDA). Levels in plasmas= micromoles/L.
Efficacy of treatment
Absolute change in hepatic iron concentration EOS versus baseline.
Evolution of iron overload serologic markers
Absolute and relative changes in serum ferritin and transferrin saturation from baseline to every visit during the whole treatment period
Evolution of toxic serum iron forms
Presence and quantitative evolution of toxic serum iron forms (iron tissue reactive species) under low dose DFX therapy
Relationship between NTBI and LPI with serum ferritin and liver and pancreas iron overload
Prevention of iron overload will be studied by the difference iron parameters end of therapy - baseline by liver iron concentration (mg/g dry weight), pancreas iron concentration (mg/g dry weight), total body iron stores (mg/kg) calculated the N Engl J med 2000 343:327-331 formula = liver iron concentration x 10.6.
Serum ferritin = ng/ml.
Relationship between suppression of tissue iron species and prevention of iron accumulation (observational study) will be measured by the:
NTBI/LPI values (micromoles/L), Differences end of study - baseline quantitative parameters of iron loading (liver and pancreas iron concentration and total body iron stores).
Overall safety of deferasirox
Evaluate the overall safety of deferasirox FCT formulation in patients with lower risk MDS at the beginning of their transfusional history
Leukemic transformation
Leukemic transformation (progression to leukemia or higher rIPSS scores)
Hemopoietic response
Percentage of patients with hematologic improvements in term of erythroid response following IWG 2006 criteria.
Costs analysis
Treatment cost will be compared with standard approach cost (14 mg/kg/day. DFX-FCT after 20 units of packed red cells units and serum ferritin> 1000 ng/ml over one year of treatment). For comparison literature and matched FISM registry data will be used. Unit of measurement will be 2019 USD and Euros.
Study of biological cellular damage
Biological cellular damage will be measured by presence and level of oxidative stress determined at baseline, during and at end of study and compared with ongoing treatment by: Malonildialdehyde (MDA) plasma levels (micromoles/L).
Full Information
NCT ID
NCT03920657
First Posted
December 14, 2018
Last Updated
November 16, 2022
Sponsor
Fondazione Italiana Sindromi Mielodisplastiche-ETS
1. Study Identification
Unique Protocol Identification Number
NCT03920657
Brief Title
Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS
Official Title
Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS
Study Type
Interventional
2. Study Status
Record Verification Date
March 2021
Overall Recruitment Status
Terminated
Why Stopped
enrollment failed
Study Start Date
October 4, 2019 (Actual)
Primary Completion Date
October 6, 2020 (Actual)
Study Completion Date
April 22, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fondazione Italiana Sindromi Mielodisplastiche-ETS
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The scientific rationale for this study is the evolving understanding that iron-induced tissue damage is not only a process of progressive bulking of organs through high-volumes iron deposition, but also a reactive iron species related "toxic" damage.
Iron mediated damage can occur prior reaching high iron storage thresholds derived from thalassemia major setting, free toxic iron species being already present when transferrin saturation >60-70% (25); therefore a timely early adoption of iron chelation may be of benefit before overt iron overload is seen.
Our hypothesis is that early and low dose DFX-FCT is better tolerated and is able to prevent iron accumulation and consequently tissue iron related damage, by consistently suppressing iron reactive oxygen species (NTBI and LPI).
If this hypothesis is confirmed this approach could contribute to an improvement of clinical practice of patients managements. Additionally this approach might also be a contribute in preventing future iron overloaded related complication, in this already frail and co-treated patient population.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes
Keywords
MDS
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
This is an open-label, single arm, phase II, study designed to look whether early intervention with low dose DFX improves clinical outcome of patients with MDS.
Masking
None (Open Label)
Allocation
N/A
Enrollment
11 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Deferasirox
Arm Type
Experimental
Arm Description
patients will be assigned to a fixed dose of 3.5 mg/kg/day of DFX FCT.
Intervention Type
Drug
Intervention Name(s)
Deferasirox
Other Intervention Name(s)
Exjade
Intervention Description
Fixed dose of 3.5 mg/kg/day of DFX FCT
Primary Outcome Measure Information:
Title
Change of hepatic iron
Description
Change of hepatic iron from the baseline according to baseline hepatic iron level: For patients with baseline LIC ≤5 mg/g dry weight (dw) ± 1.5 mg/g dw. For patients with baseline LIC >5 mg/g dw ±20%
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Definition of iron overload
Description
The baseline iron status of MDS patients at the beginning of their transfusion story is today unknown. This study is the first unbiased and direct measurement of iron stress and oxidative stress in MDS patients at the beginning of the transfusion story.
Baseline iron status will be described by classical iron markers:
serum ferritin (ng/ml), transferritin saturation (%), liver and pancreas iron concentration by MRI (mg/g dry weight). Total body iron stores will be calculated (mg/kg) with the published formula (N Engl J Med 2000; 343:327-331).
Tissue reactive oxygen species will be measured in the patient's plasma as follows:
non-transferrin bound iron= micromoles/L, Labile Plasma Iron= micromoles/L. Oxidative stress will be measured by Malonildialdehyde (MDA). Levels in plasmas= micromoles/L.
Time Frame
1 year
Title
Efficacy of treatment
Description
Absolute change in hepatic iron concentration EOS versus baseline.
Time Frame
1 year
Title
Evolution of iron overload serologic markers
Description
Absolute and relative changes in serum ferritin and transferrin saturation from baseline to every visit during the whole treatment period
Time Frame
1 year
Title
Evolution of toxic serum iron forms
Description
Presence and quantitative evolution of toxic serum iron forms (iron tissue reactive species) under low dose DFX therapy
Time Frame
1 year
Title
Relationship between NTBI and LPI with serum ferritin and liver and pancreas iron overload
Description
Prevention of iron overload will be studied by the difference iron parameters end of therapy - baseline by liver iron concentration (mg/g dry weight), pancreas iron concentration (mg/g dry weight), total body iron stores (mg/kg) calculated the N Engl J med 2000 343:327-331 formula = liver iron concentration x 10.6.
Serum ferritin = ng/ml.
Relationship between suppression of tissue iron species and prevention of iron accumulation (observational study) will be measured by the:
NTBI/LPI values (micromoles/L), Differences end of study - baseline quantitative parameters of iron loading (liver and pancreas iron concentration and total body iron stores).
Time Frame
1 year
Title
Overall safety of deferasirox
Description
Evaluate the overall safety of deferasirox FCT formulation in patients with lower risk MDS at the beginning of their transfusional history
Time Frame
1 year
Title
Leukemic transformation
Description
Leukemic transformation (progression to leukemia or higher rIPSS scores)
Time Frame
1 year
Title
Hemopoietic response
Description
Percentage of patients with hematologic improvements in term of erythroid response following IWG 2006 criteria.
Time Frame
1 year
Title
Costs analysis
Description
Treatment cost will be compared with standard approach cost (14 mg/kg/day. DFX-FCT after 20 units of packed red cells units and serum ferritin> 1000 ng/ml over one year of treatment). For comparison literature and matched FISM registry data will be used. Unit of measurement will be 2019 USD and Euros.
Time Frame
1 year
Title
Study of biological cellular damage
Description
Biological cellular damage will be measured by presence and level of oxidative stress determined at baseline, during and at end of study and compared with ongoing treatment by: Malonildialdehyde (MDA) plasma levels (micromoles/L).
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis: Adult Myelodysplastic Syndrome (≥18 years).
Revised IPSS: very low. low - intermediate
Having received 5-20 packed red blood cell units
Serum ferritin ≥300 ng/ml
Transferrin saturation ≥ 60%
Chelation naïve
Capability to provide informed consent
Exclusion Criteria:
Patients aged <18 years old
Higher risk (revised IPSS) MDS (Intermediate 2, high)
Cumulative transfusion story of > 20 packed red cell units
Creatinine Clearance (CrCL): <60 ml/min. Patients with CrCl of 40-60ml/min will be included only individually if no other renal risk factors are present.
Serum creatinine >2 x ULN at screening. If borderline serum creatinine will be measured within 7-10 days and the mean value will be used for eligibility criteria.
Significant proteinuria as indicated by a urinary protein/creatinine ratio > 0.5 mg/mg in a non-first void urine sample (or alternatively in two of three samples obtained for screening).
ECOG performance status >2.
Left ventricular ejection fraction < 50% by echocardiography
A history of repeated hospitalization for congestive heart failure.
Systemic diseases that would prevent study treatment (e.g. uncontrolled hypertension, cardiovascular, renal, hepatic, metabolic, etc.)
Clinical or laboratory evidence of chronic Hepatitis B or Hepatitis C (definition of chronic hepatitis follows EASL 2017 criteria).
History of HIV positive test result (ELISA or Western blot).
Treatment with systemic investigational drug within 4 weeks or topical investigational drug within 7 days of study start.
ALT or AST over 3 times superior to ULN at screening.
ANC < 500/ microL
Platelets transfusion dependency
Total bilirubin over 1.5 times superior to ULN at screening (patients with Gilbert syndrome are allowed to enter the study)
Diagnosis of Child score C liver cirrhosis.
Patients participating in another clinical trial other than an observational registry study.
Patients with a history of another malignancy within the past 3 years, with the exception of basal skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ.
History of non-compliance to medical regimens, or patients who are considered potentially unreliable and/or not cooperative.
Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug.
Pregnant, intending-to-become pregnant, or breast-feeding patients.
Women of potential maternity age who do not agree to practice effective contraceptive methods fo the entire study duration.
History of drug or alcohol abuse within the 12 months prior to enrollment.
Hypersensitivity to the active substance or to any of the excipients.
Inability to provide a valid informed consent
Facility Information:
Facility Name
S.O.D. Ematologia Policlino Careggi
City
Firenze
State/Province
FI
ZIP/Postal Code
50134
Country
Italy
Facility Name
Medicina Interna II Divisione di Ematologia, Ospedale S. Luigi Gonzaga
City
Orbassano
State/Province
TO
ZIP/Postal Code
10043
Country
Italy
Facility Name
Ematologia - Spedali Civili
City
Brescia
ZIP/Postal Code
25100
Country
Italy
Facility Name
Ospedale Businco
City
Cagliari
Country
Italy
Facility Name
Ospedale San Martino
City
Genova
Country
Italy
Facility Name
Ospedale Niguarda
City
Milano
Country
Italy
Facility Name
Azienda Ospedaliera di Padova
City
Padova
ZIP/Postal Code
35128
Country
Italy
Facility Name
AO Bianchi Melacrino Morelli
City
Reggio Calabria
ZIP/Postal Code
89125
Country
Italy
Facility Name
Ospedale S. Eugenio
City
Roma
Country
Italy
Facility Name
Istituto clinico Humanitas
City
Rozzano (MI)
Country
Italy
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Early and Low Dose Deferasirox (3.5 mg/kg FCT) to Suppress NTBI and LPI as Early Intervention to Prevent Tissue Iron Overload in Lower Risk MDS
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