Pilot Study for Patients With Poor Response to Deferasirox

• Sponsor: Boston Children's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00749515
• Collaborator: Novartis (Industry)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 8
• Patients Per Site Per Month: 1.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Transfusion-dependent Hemachromatosis; Thalassemia Major; Sickle Cell Disease	Drug: Deferoxamine; Drug: Deferasirox; Radiation: HIDA	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Pharmacokinetic Study In Patients With Inadequate Response To Deferasirox (Exjade)
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single Arm All patients received the same interventions of deferoxamine challenge, deferasirox dose with pharmacokinetic monitoring and HIDA scan. Then we compared responses between patients who were known to be slow responders to deferasirox and those who were known to be rapid responders (chelated well).

Drug: Deferoxamine; 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.; Other Names: Desferal ; Drug: Deferasirox; 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.; Other Names: Exjade ICL670 ; Radiation: HIDA; All patients had a HIDA scan to assess physiologic liver clearance capacity.

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve of Deferasirox After a Dose of 35 mg/kg [0, 1, 2, 4, 6, 8, 12, and 24 hours post dose]

   Area Under the Curve (AUC) 0 to 24 hours post dose

2. Half-Life of Deferasirox [0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.]

   All patients received the same interventions of deferoxamine challenge, deferasirox dose with pharmacokinetic monitoring. Then we compared responses between patients who were known to be slow responders to deferasirox and those who were known to be rapid responders (chelated well). Deferoxamine: 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.

3. Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg [0, 1, 2, 4, 6, 8, 12, and 24 hours post dose]

   Volume of distribution/bioavailability (Vd/F)

4. Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg [0, 1, 2, 4, 6, 8, 12, and 24 hours post dose]

   Volume of distribution/bioavailability (Vd/F), adjusted per kilogram body weight

5. Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg [0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.]

   Clearance/bioavailability (CL/F)

Secondary Outcome Measures

1. Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition [3 months]

   Polymorphisms in genes known to be, or potentially involved, in deferasirox disposition: UGT1a1 (including the Gilbert syndrome promoter polymorphism, (TA)nTAA),UGT1a3, BRCP/ABCG2, MRP2/ABCC2. These genes were chosen because deferasirox is primarily eliminated by glucuronidation and subsequent biliary excretion.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Boston	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Boston Children's Hospital
• Novartis

Investigators

• Principal Investigator: Deborah Chirnomas, MD, Boston Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ellis Neufeld, Professor of Pediatrics, Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT00749515
• Other Study ID Numbers: 07090349; NIH/NHLBI 1 K12 HL087164-01
• First Posted: Sep 9, 2008
• Last Update Posted: Jun 25, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Ellis Neufeld, Professor of Pediatrics, Boston Children's Hospital: Thalassemia; Iron; Chelation
• Additional relevant MeSH terms: Anemia, Sickle Cell; Thalassemia; beta-Thalassemia; Hemochromatosis; Hemosiderosis; Deferasirox; Deferoxamine

Study Results

Participant Flow

Recruitment Details	Between March 2008 and June 2008, 15 patients were recruited who had transfusional iron overload, and had been on deferasirox for at least 6 months at some point in their chelation history. Ten (10) patients were recruited as inadequate responders and 5 were recruited as control patients with adequate response to deferasirox therapy.

Arm/Group Title	Inadequate Responders	Adequate Responders (Control)
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.	Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Period Title: Overall Study
STARTED	10	5
COMPLETED	10	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Inadequate Responders	Adequate Responders (Control)	Total
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.	Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.	Total of all reporting groups
Overall Participants	10	5	15
Age (Count of Participants)
<=18 years	7 70%	2 40%	9 60%
Between 18 and 65 years	3 30%	3 60%	6 40%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	3 30%	2 40%	5 33.3%
Male	7 70%	3 60%	10 66.7%
Region of Enrollment (participants) [Number]
United States	10 100%	5 100%	15 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve of Deferasirox After a Dose of 35 mg/kg
Description	Area Under the Curve (AUC) 0 to 24 hours post dose
Time Frame	0, 1, 2, 4, 6, 8, 12, and 24 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inadequate Responders	Adequate Responders (Control)
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.	Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Measure Participants	10	5
Mean (Standard Deviation) [micromole/liter*hour]	479.59 (259.42)	1123.11 (63.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inadequate Responders, Adequate Responders (Control)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Half-Life of Deferasirox
Description	All patients received the same interventions of deferoxamine challenge, deferasirox dose with pharmacokinetic monitoring. Then we compared responses between patients who were known to be slow responders to deferasirox and those who were known to be rapid responders (chelated well). Deferoxamine: 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.
Time Frame	0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inadequate Responders	Adequate Responders (Control)
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.	Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Measure Participants	10	5
Mean (Standard Deviation) [hour]	6.08 (2.01)	7.83 (2.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inadequate Responders, Adequate Responders (Control)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.275
	Comments
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
Description	Volume of distribution/bioavailability (Vd/F)
Time Frame	0, 1, 2, 4, 6, 8, 12, and 24 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inadequate Responders	Adequate Responders (Control)
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.	Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Measure Participants	10	5
Mean (Standard Deviation) [liter]	10.33 (7.42)	6.5 (2.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inadequate Responders, Adequate Responders (Control)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.178
	Comments
	Method	t-test, 2 sided
	Comments

4. Primary Outcome

Title	Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg
Description	Volume of distribution/bioavailability (Vd/F), adjusted per kilogram body weight
Time Frame	0, 1, 2, 4, 6, 8, 12, and 24 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inadequate Responders	Adequate Responders (Control)
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.	Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Measure Participants	10	5
Mean (Standard Deviation) [liter/kilogram]	0.32 (0.25)	0.13 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inadequate Responders, Adequate Responders (Control)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.062
	Comments
	Method	t-test, 2 sided
	Comments

5. Primary Outcome

Title	Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg
Description	Clearance/bioavailability (CL/F)
Time Frame	0, 1, 2, 4, 6, 8, 12, and 24 hours post dose.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inadequate Responders	Adequate Responders (Control)
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.	Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Measure Participants	10	5
Mean (Standard Deviation) [liter/hour]	1.30 (.18)	0.61 (0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inadequate Responders, Adequate Responders (Control)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.104
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition
Description	Polymorphisms in genes known to be, or potentially involved, in deferasirox disposition: UGT1a1 (including the Gilbert syndrome promoter polymorphism, (TA)nTAA),UGT1a3, BRCP/ABCG2, MRP2/ABCC2. These genes were chosen because deferasirox is primarily eliminated by glucuronidation and subsequent biliary excretion.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inadequate Responders	Adequate Responders (Control)
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.	Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
Measure Participants	10	5
UGT1a1	10 100%	5 100%
UGT1a3	10 100%	5 100%
BCRP/ABCG2	10 100%	5 100%
MRP2/ABCC2	10 100%	5 100%

Adverse Events

Time Frame	Adverse event are reported for at least 28 days following the last dose of study drug.
Arm/Group Title	Inadequate Responders		Adequate Responders (Control)
Arm/Group Description	Patients having a rising ferritin trend over 3 consecutive months, at least one higher than 1500ng/mL (1500 µg/L) or rising liver iron documented by biopsy or change in T2 or Ferriscan magnetic resonance imaging (MRI) and on a dose of more than 30img/kg per day of deferasirox.		Patients having a ferritin trend below 1000 ng/mL (1000 µg/L) or documented declining liver iron burden by MRI or biopsy and on a dose of 30img/kg per day or less of deferasirox.
All Cause Mortality
	Inadequate Responders		Adequate Responders (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/5 (0%)
Serious Adverse Events
	Inadequate Responders		Adequate Responders (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Inadequate Responders		Adequate Responders (Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.