Study of Deferasirox for Treatment of Transfusional Iron Overload in Myelodysplastic Patients

Study Overview
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Brief Summary
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The purpose of this trial is to examine the safety and efficacy of deferasirox in patients with Myelodysplastic Syndrome (MDS) and chronic iron overload from blood transfusions.

Detailed Description
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Study entry requires a diagnosis of low or intermediate (INT-1) risk MDS per International Prognostic Scoring System (IPSS) criteria and serum ferritin ≥ 1000 ng/mL. Patients must have had at least 30 prior red blood cell transfusions. Deferasirox will be administered at an initial dose of 20 mg/kg orally once per day. Patient transfusion history and at least three complete blood count (CBC) values must be available for the 12 weeks prior to study registration for patients with MDS and chronic iron overload from blood transfusions.

Official Title
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An Open Label, Safety and Tolerability Study of Deferasirox for Treatment of Transfusional Iron Overload in Low-risk and INT-1, Myelodysplastic Patients Using Serum Ferritin Monitoring

Conditions
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Myelodysplastic Syndrome, Iron Overload

Intervention / Treatment
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* Drug: Deferasirox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients with low or intermediate (INT-1) risk MDS Patients can be EITHER naïve to iron chelation OR have had prior treatment with deferoxamine (DFO). Age greater than or equal to 18 years Availability of transfusion records for the 12 weeks prior to registration A lifetime minimum of 30 previous packed red blood cell transfusions Availability of at least three CBC values (pretransfusion) during the 12 weeks prior to registration Serum Ferritin: For entry into the screening period, serum ferritin ≥ 1000 ng/mL on at least two occasions, at least two weeks apart, during the prior year. Serum ferritin ≥ 1000 ng/mL at screening via the central lab. Life expectancy ≥ 6 months Sexually active women must use an effective method of contraception, or must have undergone clinically documented total hysterectomy and/or oophorectomy, or tubal ligation or be postmenopausal (defined as amenorrhea for at least 12 months) Able to provide written informed consent Exclusion Criteria: Serum creatinine above the upper limit of normal Alanine aminotransferase (ALT) > 500 U/L during screening Clinical or laboratory evidence of active Hepatitis B or C Urinary protein/creatinine ratio > 0.5 mg/mg History of HIV positive test result (ELISA or Western blot) Eastern Cooperative Oncology Group (ECOG) Performance Status > 2 Patients with uncontrolled systemic hypertension Unstable cardiac disease not controlled by standard medical therapy Patients with a diagnosis of or history of clinically relevant ocular toxicity related to iron chelation Systemic diseases (cardiovascular, renal, hepatic, etc.) which would prevent study treatment Pregnancy or breast feeding Treatment with systemic investigational drug within the past 4 weeks or topical investigational drug within the past 7 days Other surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug History of non-compliance to medical regimens or patients who are considered potentially unreliable and/or not cooperative

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ICL670<br>Evaluate the safety and tolerability of deferasirox 20 mg/kg/day over one year in patients with MDS | Drug: Deferasirox<br>* 20 mg/kg/day over one year in patients with MDS<br>* Other names: iron chelation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Adverse Events | Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the study, whether or not considered related to the participant's participation in the study. Serious Adverse Events include adverse events that result in either of death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. | up to 53 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Ferritin From Baseline to Weeks 13, 25, 37 and 53 | Change in levels of serum ferritin from baseline to 3, 6, 9 and 12 months (Weeks 13, 25, 37 and 53). | From Baseline to Weeks 13, 25, 37 and 53 | 
| Change in Labile Plasma Iron (LPI) | LPI represents the component of non-transferrin bound iron and is an indicator of iron overload. The blood sample for LPI determinations was collected at Week 1 (prior to first dose) and at Weeks 13, 25, 37 and 49. LPI was calculated as 1 LPI unit = the quantity of reactive oxygen species produced by approximately 1.5 μM Fe | From Baseline to Weeks 13, 25, 37 and 49 | 
| Directly Chelatable Iron (DCI) | The blood sample for DCI determinations were collected at Week 1 (prior to first dose) and at Weeks 13, 25, 37 and 49. | From Baseline to Weeks 13, 25, 37 and 49 | 
| Total Iron Levels | Levels of non-transferrin bound iron (NTBI) and serum iron from baseline to 3,6,9 and 12 months (Weeks 13, 25, 37 and 49) were assessed. | From Baseline to Weeks 13, 25, 37, 49 and 53 | 
| Serum Transferrin Levels | Serum transferrin from baseline to 3, 6, 9 and 12 months of treatment (Visit Weeks 13, 25, 37 and 49) were assessed. | From Baseline to Weeks 13, 25, 37, 49 and 53 | 
| Transferrin Saturation | Levels of transferrin saturation from baseline to 3, 6, 9 and 12 months. | From Baseline to Weeks 13, 25, 37, 49 and 53 | 
| Transfusion Requirements | Number of participants receiving transfusions, the summarized during the study. | up to 1 year | 
| Frequency of Hematologic Improvement During the Study | Hematologic responses defined by International Working Group response criteria in myelodysplasia. Hematologic Improvement (HI) responses, at least 9 weeks defined as: Erythroid response (pretreatment, <11 g/dL): Hgb increase by 1.5 g/dL; Relevant reduction units of Red blood cell (RBC) transfusions by absolute number at least 4 RBC transfusions/8 week compared with pretreatment transfusion number in previous 8 weeks; Only RBC transfusions for Hgb of 9.0 g/dL pretreatment count in RBC transfusion response evaluation; Platelet response (pretreatment,<100x10^9/L): If starting with >20x10^9/L platelets: absolute increase 30x10^9/L, Increase from baseline <20 x10^9/L to >20x10^9/L and by =/> 100%; Neutrophil response (pretreatment, <1.0x10^9/L): =/> 100% increase & absolute increase >0.5x10^9/L; Progression or relapse after HI: At least 1 of the following: =/>50% decrement from max response levels in granulocytes or platelets; Reduction in Hgb by 1.5 g/dL; or Transfusion dependence. | up to 1 year | 
| Trough Plasma Deferasirox Concentration | The Pharmacokinetic (PK) parameters were assessed at Week 13, 25, 37 and 49 using Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) method. | At Week 13, 25, 37 and 49 | 
| Treatment Compliance to Deferasirox | Treatment compliance was assessed using records of study medication used, dosages administered, and intervals between visits during the study. Drug accountability was noted by the field monitor during site visits and at the completion of the trial. Participants were asked to return all unused medication at monthly visits. | up to 1 year | 
| The Prevalence of Hereditary Hemochromatosis Gene (HFE) Gene Mutations | HFE (hemochromatosis) gene mutations in the Myelodysplastic Syndrome (MDS) population, the trial included testing for the C282Y, H63D and S65C HFE gene mutations. One blood sample was collected at Baseline (Week 1), or, if that visit was missing, the sample was taken at Week 13 (Month 3). Only one blood sample was to be taken from each participant. | up to Week 13 (Month 3) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICL670, Deferasirox, Iron chelation, Chelator, Desferal