Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.

An Open-label, Phase II, Randomized, Pilot Study to Assess the Effect in Term of Erythroid Improvement of Deferasirox Combined With Erythropoietin Compared to Erythropoietin Alone in Patients With low-and Int-1-risk Myelodysplastic Syndrome.

The primary purpose of this trial was is to assess the effect of treatment with deferasirox combined with erythropoietin vs. erythropoietin alone on erythropoiesis in patients with low- and int-1-risk myelodysplastic syndrome. The addition of deferasirox to erythropoietin can lead to a potential synergism with the reduction of reactive oxygen species, through both the NF-kB pathway and the control of free toxic iron. This may create a better environment in the bone marrow for a better response with erythropoietin.

This study was designed to test in a prospective way the combination of deferasirox with erythropoietin in terms of their effect on hematopoiesis.

Study Overview

• Status: Completed
• Conditions: Low and Int 1-risk Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Erythropoietin alpha; Drug: Deferasirox DFX, DT; Drug: Deferasirox DFX, FCT

Detailed Description

This study did not meet the original enrollment objective of 60 patients and was terminated without extending enrollment past original planned LPFV of 31-Oct-2016.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• Algeria
  • Oran, Algeria, 31000
    • Novartis Investigative Site
  • Sidi Bel abbes, Algeria, 22000
    • Novartis Investigative Site
• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1425DND
      • Novartis Investigative Site
    • La Plata, Buenos Aires, Argentina, B1900AWT
      • Novartis Investigative Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z1Y6
      • Novartis Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
• China
  • Shanghai, China, 200025
    • Novartis Investigative Site
  • Beijing
    • Beijing, Beijing, China, 100730
      • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 51000
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Novartis Investigative Site
• Germany
  • Berlin, Germany, 12203
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Duesseldorf, Germany, 40225
    • Novartis Investigative Site
  • Lütten-Klein, Germany, 18107
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
• Italy
  • CA
    • Cagliari, CA, Italy, 09126
      • Novartis Investigative Site
  • RC
    • Reggio Calabria, RC, Italy, 89124
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00161
      • Novartis Investigative Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 06351
      • Novartis Investigative Site
• Spain
  • Catalunya
    • Badalona, Catalunya, Spain, 08916
      • Novartis Investigative Site
    • Girona, Catalunya, Spain, 17007
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
• Sweden
  • Gothenburg, Sweden, 413 45
    • Novartis Investigative Site
  • Linköping, Sweden, SE-581 85
    • Novartis Investigative Site
  • Lulea, Sweden, SE 971 80
    • Novartis Investigative Site
  • Stockholm, Sweden, SE-141 86
    • Novartis Investigative Site
• United Kingdom
  • Lancashire
    • Oldham, Lancashire, United Kingdom, OL1 2JH
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Patients who had low- and Int-1-risk myelodysplastic syndrome
• Documented diagnosis of the following:

Myelodysplastic syndrome that lasted ≥ 3 months and < 3 years Disease must not have been secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases

• A hemoglobin < 10 g/dL and ≥ 8 g/dL
• History of transfusions < 10 RBC units and must not have been RBC transfusion dependent
• 300 ng/mL < serum ferritin < 1,500 ng/mL (Values within 10% difference above 1500 ng/ml or 10% difference below 300 ng/ml could have been accepted at the investigator's discretion.
• Endogenous erythropoietin levels < 500 units/L
• Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
• Creatinine clearance above the concentration limit in locally approved prescribing information (PI). Patients with creatinine clearance between 40 and less than 60 mL/min, who did not present with additional risk factors that might impair renal function, were eligible at the discretion of the investigator

Key Exclusion Criteria:

• Patients who had MDS with isolated del(5q)
• Patients who had received prior EPO treatment or other recombinant growth factors regardless of the outcome (Patient who had received prior EPO treatment or other recombinant growth factors for less than 4 weeks and not within 3 months before screening without a documented response are allowed)
• Patients who had received steroids or immunosuppressive therapy for the improvement of hematological parameters (stable steroid treatment for adrenal failure or chronic medical conditions, and intermittent dexamethasone as antiemetics were allowed).
• B12 and folate deficient patients with and without clinical symptoms (patients were rescreened after successful therapy of B12 and folate deficiency)
• Uncontrolled seizures or uncontrolled hypertension

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Erythropoietin alpha; Patients will receive erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be switched to the combination arm. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study.	Drug: Erythropoietin alpha
Experimental: Deferasirox + Erythropoietin alpha; Patients will receive deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet (FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, erythropoietin dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be discontinued from the study. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study. Patients will continue deferasirox treatment.	Drug: Deferasirox DFX, DT; provided as dispersible tablets for oral use in 125 and 250, 500 mg; Drug: Deferasirox DFX, FCT; provided as film-coated tablet for oral use in 90, 180, 360 mg strengths

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Percentage of Patients Achieving Erythroid Response Within 12 Weeks, by Treatment Group (Full Analysis Set)	Difference in percentage of patients achieving an erythroid response within 12 weeks of treatment between the two arms according to modified IWG 2006 criteria increase in hemoglobin (Hb) ≥ 1.5 g/dL. Erythroid response is defined as the increase in Hb from baseline ≥ 1.5 g/dL. Patients achieving erythroid response at least once within 12 weeks were considered responders	Baseline up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline to Post-baseline Value for Hemoglobin(g/dL)(Full Analysis Set)	Hematological response criteria defined as: Erythroid response: hemoglobin (Hb) increase from baseline >= 1.5 g/dL (baseline < 11 g/dL), neutrophil response: increase from baseline >= 100% and increase > 0.5 × 10^9/L (baseline <1 × 10^9/L), platelet response: increase from baseline >= 30 × 10^9/L (baseline <100 × 10^9/L) according to modified IWG 2006 criteria	Baseline up to 24 weeks
Summary of Hematologic Improvement in Patients Randomized to EPO+DFX and EPO Alone, Within 24 Weeks of Treatment (Full Analysis Set)	Percentage of participants achieving an hematologic improvement defined as: neutrophil improvement: increase from baseline >0.5 × 10^9/L (baseline = 1.0 × 10^9/L ), platelet improvement: increase from baseline ≥ 30 × 10^9/L (baseline = 100 × 10^9/L), hemoglobin improvement: Hb increase from baseline ≥ 1 g/dL (baseline<11 g/dL)	Baseline up to 24 weeks
Absolute Change in Hemoglobin Values up to 24 Weeks	Absolute change in hemoglobin values for patients showing improvement: Hemoglobin improvement Hb increase from baseline ≥ 1 g/dL (baseline<11 g/dL)	Baseline up to 24 weeks
Absolute Change in Platelets and Neutrophil Levels up to 24 Weeks	Absolute change in platelets and neutrophil levels for participants showing improvement: neutrophil improvement: increase from baseline >0.5 × 10^9/L (baseline = 1.0 × 10^9/L ), platelet improvement: increase from baseline ≥ 30 × 10^9/L (baseline = 100 × 10^9/L)	Baseline up to 24 weeks
Summary of Erythroid Response in Participants Randomized to EPO Alone at Baseline and Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)	Erythroid response: hemoglobin increase from baseline > = 1.5 g/dL (baseline <11 g/dL)	Week 13 up to 24 weeks
Summary of Erythroid Response Within 24 Weeks in Participants Randomized to EPO at Baseline and Not Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)	Erythroid response: hemoglobin increase from baseline > = 1.5 g/dL (baseline <11 g/dL). Percentages are based on N. Confidence intervals are calculated using Clopper-Pearson method. Hemoglobin value is at time of first response	baseline up to 24 weeks
Absolute Change in Serum Ferritin up to 24 Weeks for Erythropoietin Alpha Arm (Full Analysis Set)	Absolute change in serum ferritin from baseline	Baseline up to 24 weeks
Absolute Change in Serum Ferritin up to 24 Weeks for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)	Absolute change in serum ferritin from baseline	Baseline up to 24 weeks
Absolute Change in Serum Ferritin up to 24 Weeks for EPO+DFX at 12 Weeks Arm (Full Analysis Set)	Absolute change in serum ferritin from baseline	Baseline up 24 weeks
Absolute Change in Hemoglobin (Hb) From Baseline for Erythropoietin Alpha Arm (Full Analysis Set)	This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.	Baseline up to 24 weeks
Absolute Change in Hemoglobin (Hb) From Baseline for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)	This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.	Baseline up to 24 weeks
Absolute Change in Hemoglobin (Hb) From Baseline for EPO+DFX at 12 Weeks Arm (Full Analysis Set)	This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders.	Baseline up to 24 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2014
• Primary Completion (Actual): March 22, 2017
• Study Completion (Actual): April 5, 2017

Study Registration Dates

• First Submitted: May 30, 2013
• First Submitted That Met QC Criteria: May 30, 2013
• First Posted (Estimate): June 4, 2013

Study Record Updates

• Last Update Posted (Actual): October 31, 2018
• Last Update Submitted That Met QC Criteria: October 4, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: adult; erythropoietin; MDS; myelodysplasia; deferasirox; myelodysplastic syndrome; erythropoiesis; blood disorder; cytopenias; low blood counts; progressive bone marrow failure; ICL570; NF-kB pathway; hematopoiesis.
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Hematinics; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Epoetin Alfa; Deferasirox
• Other Study ID Numbers: CICL670A2421