Iron Overload, Myelodysplastic Syndrome
Conditions
Keywords
ICL670, Deferasirox, Iron chelation, Chelator, Desferal
Brief summary
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
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.
Interventions
DRUGDeferasirox
20 mg/kg/day over one year in patients with MDS
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Adverse Events | up to 53 Weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Ferritin From Baseline to Weeks 13, 25, 37 and 53 | 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). |
| Change in Labile Plasma Iron (LPI) | From Baseline to Weeks 13, 25, 37 and 49 | 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 |
| Directly Chelatable Iron (DCI) | From Baseline to Weeks 13, 25, 37 and 49 | The blood sample for DCI determinations were collected at Week 1 (prior to first dose) and at Weeks 13, 25, 37 and 49. |
| Total Iron Levels | From Baseline to Weeks 13, 25, 37, 49 and 53 | 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. |
| Serum Transferrin Levels | From Baseline to Weeks 13, 25, 37, 49 and 53 | Serum transferrin from baseline to 3, 6, 9 and 12 months of treatment (Visit Weeks 13, 25, 37 and 49) were assessed. |
| Transfusion Requirements | up to 1 year | Number of participants receiving transfusions, the summarized during the study. |
| Frequency of Hematologic Improvement During the Study | up to 1 year | 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. |
| Trough Plasma Deferasirox Concentration | At Week 13, 25, 37 and 49 | The Pharmacokinetic (PK) parameters were assessed at Week 13, 25, 37 and 49 using Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) method. |
| Treatment Compliance to Deferasirox | up to 1 year | 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. |
| The Prevalence of Hereditary Hemochromatosis Gene (HFE) Gene Mutations | up to Week 13 (Month 3) | 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. |
| Transferrin Saturation | From Baseline to Weeks 13, 25, 37, 49 and 53 | Levels of transferrin saturation from baseline to 3, 6, 9 and 12 months. |
Countries
Canada, United States
Participant flow
Recruitment details
The study was conducted at 39 centers in the United States and 6 centers in Canada
Pre-assignment details
A total of 176 participants enrolled in the study, of these 173 participants were treated. Three of the enrolled participants were not treated as 2 withdrew the consent and 1 died even before initiating the treatment. Of the 173 treated participants, 95 completed the study and 78 discontinued treatment prematurely.
Participants by arm
| Arm | Count |
|---|---|
| Deferasirox Participants received Deferasirox 20 mg/kg/day orally OD for one year. The appropriate daily dose was calculated by participants actual body weight. Deferasirox was taken every morning 30 minutes before breakfast, preferably around the same time between 7:00 and 9:00 AM each day. The tablets was dropped into water or apple juice or orange juice and gently stirred for 1 to 3 minutes until completely dispersed. | 173 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abnormal laboratory value | 15 |
| Overall Study | Adverse Event | 27 |
| Overall Study | Death | 17 |
| Overall Study | Participant condition no longer requires study drug | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 2 |
| Overall Study | Withdrawal by Subject | 16 |
Baseline characteristics
| Characteristic | Deferasirox |
|---|---|
| Age, Continuous | 69.9 years STANDARD_DEVIATION 11.45 |
| Race/Ethnicity, Customized Black | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 159 Participants |
| Race/Ethnicity, Customized Oriental | 4 Participants |
| Race/Ethnicity, Customized Other | 6 Participants |
| Sex: Female, Male Female | 70 Participants |
| Sex: Female, Male Male | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 17 / 173 | 1 / 3 |
| other Total, other adverse events | 166 / 173 | 0 / 3 |
| serious Total, serious adverse events | 78 / 173 | 0 / 3 |
Outcome results
Primary
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.
Time frame: up to 53 Weeks
Population: The safety population consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferasirox | Number of Participants Reporting Adverse Events | 171 Participants |
Secondary
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
Time frame: From Baseline to Weeks 13, 25, 37 and 49
Population: The full analysis set populations consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Deferasirox | Change in Labile Plasma Iron (LPI) | Baseline | 0.30 LPI Unit |
| Deferasirox | Change in Labile Plasma Iron (LPI) | Week 13 | -0.10 LPI Unit |
| Deferasirox | Change in Labile Plasma Iron (LPI) | Week 25 | -0.20 LPI Unit |
| Deferasirox | Change in Labile Plasma Iron (LPI) | Week 37 | -0.30 LPI Unit |
| Deferasirox | Change in Labile Plasma Iron (LPI) | Week 49 | -0.45 LPI Unit |
Secondary
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).
Time frame: From Baseline to Weeks 13, 25, 37 and 53
Population: The Full Analysis Set (FAS) populations consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Deferasirox | Change in Serum Ferritin From Baseline to Weeks 13, 25, 37 and 53 | Baseline | 2771.5 μg/L |
| Deferasirox | Change in Serum Ferritin From Baseline to Weeks 13, 25, 37 and 53 | Week 13 | -146.5 μg/L |
| Deferasirox | Change in Serum Ferritin From Baseline to Weeks 13, 25, 37 and 53 | Week 25 | -167.5 μg/L |
| Deferasirox | Change in Serum Ferritin From Baseline to Weeks 13, 25, 37 and 53 | Week 37 | -505.0 μg/L |
| Deferasirox | Change in Serum Ferritin From Baseline to Weeks 13, 25, 37 and 53 | Week 53 | -592.0 μg/L |
Secondary
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.
Time frame: From Baseline to Weeks 13, 25, 37 and 49
Population: The full analysis set populations consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Deferasirox | Directly Chelatable Iron (DCI) | Baseline | 0.00 µM |
| Deferasirox | Directly Chelatable Iron (DCI) | Week 13 | 0.00 µM |
| Deferasirox | Directly Chelatable Iron (DCI) | Week 25 | 0.00 µM |
| Deferasirox | Directly Chelatable Iron (DCI) | Week 37 | 0.00 µM |
| Deferasirox | Directly Chelatable Iron (DCI) | Week 49 | 0.00 µM |
Secondary
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.
Time frame: up to 1 year
Population: The analysis was performed on Per protocol population defined as number of participants who did not present any major deviations from protocol and received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deferasirox | Frequency of Hematologic Improvement During the Study | Response (Yes) | 7 Participants |
| Deferasirox | Frequency of Hematologic Improvement During the Study | Response (No) | 74 Participants |
| Deferasirox | Frequency of Hematologic Improvement During the Study | Missing | 10 Participants |
Secondary
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.
Time frame: From Baseline to Weeks 13, 25, 37, 49 and 53
Population: The full analysis set populations consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Deferasirox | Serum Transferrin Levels | Baseline | 156.0 mg/dL |
| Deferasirox | Serum Transferrin Levels | Week 13 | 161.0 mg/dL |
| Deferasirox | Serum Transferrin Levels | Week 25 | 160.0 mg/dL |
| Deferasirox | Serum Transferrin Levels | Week 37 | 158.0 mg/dL |
| Deferasirox | Serum Transferrin Levels | Week 49 | 160.0 mg/dL |
| Deferasirox | Serum Transferrin Levels | Week 53 | 161.00 mg/dL |
Secondary
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.
Time frame: up to Week 13 (Month 3)
Population: The analysis was performed on safety set population defined as all participants who received study drug and had at least one post-baseline safety assessment.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Deferasirox | The Prevalence of Hereditary Hemochromatosis Gene (HFE) Gene Mutations | C282Y | Negative | 85 Participants |
| Deferasirox | The Prevalence of Hereditary Hemochromatosis Gene (HFE) Gene Mutations | C282Y | Positive Heterozygous | 9 Participants |
| Deferasirox | The Prevalence of Hereditary Hemochromatosis Gene (HFE) Gene Mutations | H63D | Negative | 70 Participants |
| Deferasirox | The Prevalence of Hereditary Hemochromatosis Gene (HFE) Gene Mutations | H63D | Positive Heterozygous | 24 Participants |
| Deferasirox | The Prevalence of Hereditary Hemochromatosis Gene (HFE) Gene Mutations | S65C | Negative | 92 Participants |
| Deferasirox | The Prevalence of Hereditary Hemochromatosis Gene (HFE) Gene Mutations | S65C | Positive Heterozygous | 2 Participants |
Secondary
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.
Time frame: From Baseline to Weeks 13, 25, 37, 49 and 53
Population: The full analysis set populations consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Deferasirox | Total Iron Levels | Baseline | 194.0 μg/dL |
| Deferasirox | Total Iron Levels | Week 13 | 230.50 μg/dL |
| Deferasirox | Total Iron Levels | Week 25 | 222.0 μg/dL |
| Deferasirox | Total Iron Levels | Week 37 | 212.0 μg/dL |
| Deferasirox | Total Iron Levels | Week 49 | 218.0 μg/dL |
| Deferasirox | Total Iron Levels | Week 53 | 221.00 μg/dL |
Secondary
Transferrin Saturation
Levels of transferrin saturation from baseline to 3, 6, 9 and 12 months.
Time frame: From Baseline to Weeks 13, 25, 37, 49 and 53
Population: The full analysis set populations consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Deferasirox | Transferrin Saturation | Baseline | 91.00 percentage of saturation |
| Deferasirox | Transferrin Saturation | Week 13 | -11.00 percentage of saturation |
| Deferasirox | Transferrin Saturation | Week 25 | -11.00 percentage of saturation |
| Deferasirox | Transferrin Saturation | Week 37 | -12.50 percentage of saturation |
| Deferasirox | Transferrin Saturation | Week 49 | -12.00 percentage of saturation |
| Deferasirox | Transferrin Saturation | Week 53 | -18.00 percentage of saturation |
Secondary
Transfusion Requirements
Number of participants receiving transfusions, the summarized during the study.
Time frame: up to 1 year
Population: The full analysis set populations consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Deferasirox | Transfusion Requirements | Screening | 163 Participants |
| Deferasirox | Transfusion Requirements | Week 1 through 13 | 136 Participants |
| Deferasirox | Transfusion Requirements | Week 14 through 26 | 119 Participants |
| Deferasirox | Transfusion Requirements | Week 27 through 39 | 98 Participants |
| Deferasirox | Transfusion Requirements | Week 40 through 52 | 72 Participants |
Secondary
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.
Time frame: up to 1 year
Population: The analysis was performed on safety set population defined as all participants who received study drug and had at least one post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Deferasirox | Treatment Compliance to Deferasirox | 20 to < 40 % | 2 participants |
| Deferasirox | Treatment Compliance to Deferasirox | 40 - < 60 % | 1 participants |
| Deferasirox | Treatment Compliance to Deferasirox | 60 - < 80 % | 4 participants |
| Deferasirox | Treatment Compliance to Deferasirox | 80 - < 100 % | 89 participants |
| Deferasirox | Treatment Compliance to Deferasirox | 100 - < 120 % | 65 participants |
| Deferasirox | Treatment Compliance to Deferasirox | ≥ 120 % | 12 participants |
Secondary
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.
Time frame: At Week 13, 25, 37 and 49
Population: The full analysis set populations consisted of all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Deferasirox | Trough Plasma Deferasirox Concentration | Week 13 | 21.200 μmol/L |
| Deferasirox | Trough Plasma Deferasirox Concentration | Week 25 | 26.700 μmol/L |
| Deferasirox | Trough Plasma Deferasirox Concentration | Week 37 | 25.200 μmol/L |
| Deferasirox | Trough Plasma Deferasirox Concentration | Week 49 | 30.700 μmol/L |