Please select the eligibility criteria that correspond to the clinical trial below.
Title: Pilot Pharmacokinetic Study In Patients With Inadequate Response To Deferasirox (Exjade)
Brief 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.


Options:
A: Inclusion Criteria:

* Subjects with transfusional iron overload secondary to thalassemia major , sickle cell disease showing up-trend in SF aged 6 Years or older, may participate after Approval of Ethical committee giving written informed consent.
* Subjects must have a serum ferritin greater than \>2500 ng/mL, a platelet count greater than 100,000/mm3, and a serum creatinine within the normal range.
* A woman of childbearing potential must have a negative serum pregnancy test at screening. She must use a medically acceptable form of birth control during the study and for 1 month afterward.
* The subjects must also have a level of understanding and willingness to cooperate with the confinement and procedures described in the consent form and scheduled by the study site. In addition, he/she must be able to provide voluntary written informed consent.

Exclusion Criteria:

* Subjects with a past history of agranulocytosis, history of clinically significant gastrointestinal, renal, hepatic ALT \> 10 times high normal, OR \> 50% increase of serum creatinine from basal value, pulmonary or cardiovascular disease. Patients with a history of tuberculosis, epilepsy, psychosis, glaucoma or any other condition, which in the opinion of the investigators, would jeopardize the safety of the subject or impact the validity of the study results.
* Subjects with HIV positive or have active HCV.
* A history of serious immunologic hypersensitivity to any medication, such as anaphylaxis or angioedema.
* Participation in a previous investigational drug study within the 30 days preceding screening..
* Women who are pregnant, or breast-feeding.
* Current alcohol or drug abuse.
* An inability to adhere to the designated procedures and restrictions of this protocol.
* Subjects receiving warfarin, digoxin, or anti-arrhythmic or anti-seizure medications.
* Subjects with a known allergy to Exjade or DFP that prevents chronic administration.
B: 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
C: Inclusion Criteria:

* Subjects with transfusional iron overload secondary to thalassemia major, aged 18 or older, may participate after giving written informed consent. Subjects must have no clinically significant finding in their medical history, on physical examination or as a result of laboratory assessments other than those consistent with thalassemia major and its complications, such as compensated cirrhosis, endocrine insufficiency and diabetes.
* Subjects must have a serum ferritin greater than 1000 ng/mL, a platelet count greater than 100,000/mm3, and a serum creatinine within the normal range.
* Subjects must be willing and able to discontinue their usual regimen of DFO, deferiprone (L1, Ferriprox) or Exjade for the duration of the study.
* A woman of childbearing potential must have a negative serum pregnancy test at screening. She must use a medically acceptable form of birth control during the study and for 1 month afterward. Acceptable birth control measures include: abstinence, oral contraceptives, hormonal contraceptive implants, barrier contraceptives (condom, diaphragm with spermicide), IUD, and/or a vasectomized partner. Male subjects must also use barrier contraceptives during the study and for 1 month thereafter.
* The subjects must also have a level of understanding and willingness to cooperate with the confinement and procedures described in the consent form and scheduled by the study site. In addition, he/she must be able to provide voluntary written informed consent.
* Subjects must weigh at least 40 kg.

Exclusion Criteria:

* Subjects can not have a history of clinically significant gastrointestinal, renal, hepatic, endocrine, oncologic, infectious, pulmonary or cardiovascular disease, other than conditions associated with thalassemia and iron overload, such as compensated cirrhosis, endocrine insufficiency and diabetes, or a history of tuberculosis, epilepsy, psychosis, glaucoma or any other condition, which in the opinion of the investigators, would jeopardize the safety of the subject or impact the validity of the study results.
* Subjects can not be HIV positive or have active HCV.
* A history of serious immunologic hypersensitivity to any medication, such as anaphylaxis or angioedema.
* Participation in a previous investigational drug study within the 30 days preceding screening. A chelation regimen including deferiprone or Exjade within 30 days of screening would not exclude subjects coming from regions where these drugs are an approved medication.
* Women who are pregnant, or breast-feeding.
* Current alcohol or drug abuse.
* An inability to adhere to the designated procedures and restrictions of this protocol.
* Subjects with abnormal or irregular bowel function (defined as more than 3 bowel movements/day or less than 1 bowel movement every other day).
* Subjects receiving warfarin, digoxin, or anti-arrhythmic or anti-seizure medications.
* Subjects with a known allergy to Exjade or DFO that prevents chronic administration.
D: Inclusion Criteria:

* Beta-thalassemia patients already treated with or suitable for treatment with deferoxamine 20 to 40 mg/kg/day
* Liver iron content greater than 2 mg iron/g dw as measured by liver biopsy
* Need for regular transfusions 8 or more times per year

Exclusion Criteria:

* Non-transfusional iron overload or transfusion-dependent anemias other than beta-thalassemia.
* Documented toxicity to deferoxamine
* Elevated liver enzymes in the year preceeding enrollment
* Active hepatitis B or hepatitis C
* HIV seropositivity
* Elevated serum creatinine or significant proteinuria
* History of nephrotic syndrome
* Uncontrolled systemic hypertension
* Fever and other signs/symptoms of infection within 10 days prior to start of the study
* Presence of clinically relevant cataract or previous history of clinically relevant ocular toxicity related to iron chelation
* Second or third degree AV block, clinically relevant Q-T interval prolongation, or patients requiring digoxin or other drugs that prolong the Q-T interval
* Diseases (cardiovascular, renal, hepatic, etc.)that would prevent the patient from undergoing any of the treatment options
* Psychiatric or additive disorders that would prevent the patient from giving informed consent
* History of drug or alcohol abuse within the 12 months prior to the study
* Pregnant or breast feeding patients
* Patients treated with systemic investigational drugs within 4 weeks or topical investigational drugs within 7 days before the start of the study
* Any surgical or medical condition that might significantly alter the absorption, distribution, metabolism or excretion of any drug, such as gastrointestinal disease or major surgery, renal disease, difficulty voiding or urinary obstruction, or impaired pancreatic function.
* Non-compliant or unreliable patients.
* Patients unable to undergo any study procedures such as the hearing or eye tests, or the liver echocardiography.
* Inability to undergo a liver biopsy.
* Patients that would need a dose of ICL670 less than 125 mg per day.

Answer: B