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

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

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.

Study Overview

• Status: Completed
• Conditions: Iron Overload; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Deferasirox

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.

• Study Type: Interventional
• Enrollment (Actual): 176
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Novartis Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H2L 4M1
      • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Univ of Alabama Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • California
    • Concord, California, United States, 94520
      • Bay Area Cancer Research Group
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Los Angeles, California, United States, 90095-1678
      • UCLA Medical Center
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center, UCLA School of Medicine
    • San Francisco, California, United States, 94143
      • UCSF
    • San Francisco, California, United States, 94143-0324
      • UCSF
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine/Winship Cancer Institute
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Straub Clinic and Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Novartis Investigative Site
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • University of Kentucky College of Medicine, Markey Cancer Center
  • Louisiana
    • Alexandria, Louisiana, United States, 71301
      • Cabrini Center for Cancer Care/Christus St. Frances Cabrini Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21231-1000
      • St. Agnes Healthcare
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • Rush Cancer Institute Univ. of Massachussets Medical Center
  • Michigan
    • Southfield, Michigan, United States, 48075
      • Novartis Investigative Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • The Center for Cancer Care & Research (TCCCR)
  • Nebraska
    • Omaha, Nebraska, United States, 68124-2346
      • Oncology Hematology West, PC
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0001
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • The Cancer Center at Hackensack University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • NMOHC
  • New York
    • Buffalo, New York, United States, 14623
      • Roswell Park Cancer Center
    • Rochester, New York, United States, 14621
      • Rochester General Hospital/Lipson Cancer and Blood Center
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Cancer Care of WNC
    • Winston-Salem, North Carolina, United States, 27157-1082
      • Wake Forest UniversitComprehensive Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Novartis Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University; Jefferson Medical College, Kimmel Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15224
      • Western Pennsylvania Hospital Cancer Institute
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • The West Cancer Clinic
    • Nashville, Tennessee, United States, 37232
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor/The Methodist Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists
  • Virginia
    • Arlington, Virginia, United States, 22205
      • Arlington Fairfax Hematology Oncology PC
  • Washington
    • Spokane, Washington, United States, 99202
      • Novartis Investigative Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ICL670; Evaluate the safety and tolerability of deferasirox 20 mg/kg/day over one year in patients with MDS	Drug: Deferasirox; 20 mg/kg/day over one year in patients with MDS; Other Names: ICL670A; chelator; desferal; iron chelation

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• List AF, Baer MR, Steensma DP, Raza A, Esposito J, Martinez-Lopez N, Paley C, Feigert J, Besa E. Deferasirox reduces serum ferritin and labile plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J Clin Oncol. 2012 Jun 10;30(17):2134-9. doi: 10.1200/JCO.2010.34.1222. Epub 2012 Apr 30.

Helpful Links

• Results for CICL670AUS03 from the Novartis Clinical Trials website
• Publication (Embasse # 2012421150)

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 25, 2005
• Primary Completion (ACTUAL): March 28, 2008
• Study Completion (ACTUAL): March 28, 2008

Study Registration Dates

• First Submitted: May 4, 2005
• First Submitted That Met QC Criteria: May 4, 2005
• First Posted (ESTIMATE): May 5, 2005

Study Record Updates

• Last Update Posted (ACTUAL): August 16, 2021
• Last Update Submitted That Met QC Criteria: July 21, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Deferasirox; ICL670; Iron chelation; Chelator; Desferal
• Additional Relevant MeSH Terms: Metabolic Diseases; Bone Marrow Diseases; Hematologic Diseases; Iron Metabolism Disorders; Myelodysplastic Syndromes; Iron Overload; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Deferasirox
• Other Study ID Numbers: CICL670AUS03