Pilot Study for Patients With Poor Response to Deferasirox

The purpose of this trial is to examine three potential mechanisms of inadequate response to
Exjade® in patients with transfusion dependent iron overload including patients with
thalassemia syndromes, sickle cell disease and bone marrow failure.

Hypothesis: Patients have physiologic barriers to adequately respond to deferasirox that may
include absorption, pharmacokinetics of drug metabolism, hepatic clearance and/or genetic
factors.

Study objectives Primary objective

- To evaluate three potential mechanisms for inadequate response to deferasirox in a small
cohort of patients with hemoglobinopathies.

- Oral pharmacokinetics measured with Cmax and AUC following standard dose deferasirox.

- Hepatobiliary excretory function

- Accessibility of chelatable iron pool by deferoxamine challenge Secondary objective(s)

- To identify risk factors that can predict adequate response including demographics,
disease status, presence and severity of liver disease, trough levels of deferasirox at
outpatient visits and pharmacogenomics.

- To investigate usefulness of potential surrogate measures of response including serum
deferasirox levels, Hepatobiliary Iminodiacetic Acid (HIDA)nuclear medicine scan to
evaluate hepatic excretory function and urinary iron excretion by deferoxamine
challenge.

This is an investigator-initiated, pilot-scale, open-label physiological assessment of
patients who respond poorly to deferasirox compared with patients who respond well. We plan
to study 2 groups of patients: a)10 patients who have demonstrated poor responses and b) 5
control patients with good responses as defined further in the protocol. The study has two
parts.

Part I: Both groups of patients will have inpatient physiological assessments with a dose of
35mg/kg of deferasirox.

Part II: Inadequate responders eligible to continue on deferasirox will continue on a dose of
35 mg/kg for three months during which time serial pharmacokinetic levels will be studied.
The control patients will resume their previous clinically appropriate dosing (likely less
than 35 mg/kg) and for three months have serial pharmacokinetic levels drawn as well.

The study will begin with an outpatient screening visit when demographics and historical
information as well as a physical examination will be obtained and reviewed for eligibility.
At that visit patients will be able to sign informed consent. Shortly thereafter patients
will be admitted to the GCRC at Children's Hospital Boston for part I of the study, a 2-3 day
stay during which PK and nuclear medicine studies will be performed as well as the
deferoxamine urinary iron excretion challenge. Patients who are eligible will continue on to
part II of the study, and for 3 months and will be monitored for compliance, PK and ferritin
changes on appropriate deferasirox doses.

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