Pilot Study for Patients With Poor Response to Deferasirox
Condition: Transfusion-dependent Hemachromatosis; Thalassemia Major; Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell; Thalassemia; beta-Thalassemia; Hemochromatosis; Hemosiderosis
Intervention: Deferoxamine; Deferasirox; HIDA
Intervention description: After a 3-day washout period from all chelation, all patients have a 12 hour infusion of 50mg/kg of deferoxamine with urine collection and pre and post blood sampling to assess iron and Total Iron Binding Capacity (TIBC) by atomic absorption.; After a 3-day washout period from all chelation, patients had a desferal challenge which was followed by a single dose of deferasirox, 35mg/kg orally with blood sampling taken pre-deferasirox and at intervals for 24 hours after the dose.; All patients had a HIDA scan to assess physiologic liver clearance capacity.
Intervention MeSH terms: Deferasirox; Deferoxamine
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 6 Years
Healthy volunteers: No
Keywords: Thalassemia; Iron; Chelation

Summary:

      This purpose of this study is to understand the differences between people who have a good
      response to deferasirox (exjade) compared to people who have a poor response to this
      medication when used for transfusion-dependent iron overload.

      The hypothesis is that patients with poor responses have physiologic barriers to deferasirox
      that may include absorption, pharmacokinetics of drug metabolism, hepatic clearance and/or
      genetic factors.
    

Eligibility criteria:

        Part I: Inclusion criteria for Inadequate responders

          -  Male or female patients with transfusion dependent iron overload including patients
             with thalassemia syndromes, sickle cell disease and bone marrow failure.

          -  Patients currently on Desferal (desferrioxamine) therapy will require a one day wash
             out prior to the first dose of study drug.

          -  Dose of deferasirox: >30 mg/kg/day of deferasirox for at least 3 months

          -  No improvement or worsening of liver iron content (LIC) if this has been evaluated on
             deferasirox in the 3 months preceding the baseline studies.

          -  Age greater than 6 years

          -  Serum Ferritin: Ferritin >1500 ng/ml and rising over three month period while on
             deferasirox.

          -  Patients had to achieve 'failure' as described above previously and may or may not
             currently be on deferasirox and may currently be having adequate responses on doses
             greater than or equal to 35 mg/kg/day of deferasirox.

          -  Life expectancy ≥ 6 months

          -  Written informed consent by the patient or for pediatric patients consent of the
             patient's legal guardian. The definition of the term 'pediatric' for enrollment and
             study conduct will be in accordance with Children's Hospital IRB. Parents or the legal
             guardians will be fully informed by the investigator as to the requirements of the
             study. Pediatric patients themselves will be informed according to their capabilities
             in a language and in terms that they are able to understand. Written informed consent
             will be obtained from their legal guardian on the patient's behalf in accordance with
             national legislation. If capable, all patients should also personally sign their
             written informed consent.

        Part I: Inclusion criteria for good responders:

          -  Male or female patients with transfusion dependent iron overload including patients
             with thalassemia syndromes, sickle cell disease and bone marrow failure.

          -  Patients currently on Desferal (desferrioxamine) therapy will require a one day wash
             out prior to the first dose of study drug.

          -  Serum ferritin less than or equal to 1000 ng/ml or declining over a 3 month period on
             a dose of less than 30 mg/kg of deferasirox.

          -  Age greater than 6 years

          -  Life expectancy ≥ 6 months

          -  Written informed consent by the patient or for pediatric patients consent of the
             patient's legal guardian. The definition of the term 'pediatric' for enrollment and
             study conduct will be in accordance with Children's Hospital IRB. Parents or the legal
             guardians will be fully informed by the investigator as to the requirements of the
             study. Pediatric patients themselves will be informed according to their capabilities
             in a language and in terms that they are able to understand. Written informed consent
             will be obtained from their legal guardian on the patient's behalf in accordance with
             national legislation. If capable, all patients should also personally sign their
             written informed consent.

        Exclusion criteria for Part I:

          -  Pregnancy (as documented in required screening laboratory test) or breast feeding

          -  History of non-compliance to medical regimens or patients who are considered
             potentially unreliable and/or not cooperative

          -  Patients with transfusion requirements equal to or more frequent than every three
             weeks.

          -  AST or ALT > 400 U/L during screening

          -  Patients with uncontrolled systemic hypertension

          -  Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable
             cardiac or coronary artery disease not controlled by standard medical therapy

          -  Patients who received treatment with systemic investigational drug within the past 4
             weeks or topical investigational drug within the past 7 days or are planning to
             receive other investigational drugs while participating in the study

          -  Allergy to deferoxamine

          -  Known contraindication to having a nuclear medicine study

          -  Any other condition which in the opinion of the investigator would prevent completion
             of the trial.

          -  Prior possible toxicity is not an exclusion criteria for Part I because patients
             require a chelating agent of which there are only two Patients who are found to be
             ineligible after screening procedures will have this documented on the screening log.
             No further data will be collected in the CRF for these patients.

        Exclusion criteria for Part II:

          -  Patients with unacceptable toxicity to deferasirox such as renal failure or worsening
             cardiac function

          -  Patients who have failed to achieve negative iron balance at the maximum tolerated
             dose of deferasirox

          -  Patients who require an alternative chelator for specific reasons

          -  Patients who are currently enrolled on conflicting therapeutic trials

          -  Patients with serum ferritin less than 500 ng/ml at screening

          -  Any other condition which in the opinion of the investigator would prevent completion
             of the trial