Pilot Study for Patients With Poor Response to Deferasirox

• ClinicalTrials.gov Identifier: NCT00749515
• Recruitment Status: Completed
• First Posted: September 9, 2008
• Results First Posted: February 6, 2019
• Last Update Posted: June 25, 2019
• Sponsor: Boston Children's Hospital
• Collaborator: Novartis
• Information provided by (Responsible Party): Ellis Neufeld, Boston Children's Hospital

Tracking Information

• First Submitted Date: September 8, 2008
• First Posted Date: September 9, 2008
• Results First Submitted Date: June 21, 2011
• Results First Posted Date: February 6, 2019
• Last Update Posted Date: June 25, 2019
• Study Start Date: March 2008
• Actual Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 14, 2019)

• Area Under the Curve of Deferasirox After a Dose of 35 mg/kg [ Time Frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose ]
  Area Under the Curve (AUC) 0 to 24 hours post dose
• Half-Life of Deferasirox [ Time Frame: 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.
• Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg [ Time Frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose ]
  Volume of distribution/bioavailability (Vd/F)
• Volume of Distribution/Bioavailability of Deferasirox After a Dose of 35 mg/kg [ Time Frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose ]
  Volume of distribution/bioavailability (Vd/F), adjusted per kilogram body weight
• Clearance/Bioavailability of Deferasirox in Patients With Poor Response to Deferasirox Compared to Patients With Good Response After a Dose of 35 mg/kg [ Time Frame: 0, 1, 2, 4, 6, 8, 12, and 24 hours post dose. ]
  Clearance/bioavailability (CL/F)

• Original Primary Outcome Measures (submitted: September 8, 2008): Pharmacokinetics of deferasirox in patients with poor response to deferasirox compared to patients with good response after a dose of 35 mg/kg. [ Time Frame: 24 hours ]

Current Secondary Outcome Measures (submitted: June 14, 2019)

Number of Participants With Polymorphisms in Genes Known to be, or Potentially Involved, in Deferasirox Disposition [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: September 8, 2008)

• Pharmacogenomics [ Time Frame: 3 months ]
• Pharmacokinetics of clinical maintenance dose of deferasirox in poor responders to deferasirox compared to good responders. [ Time Frame: 3 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pilot Study for Patients With Poor Response to Deferasirox
• Official 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.

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 Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Transfusion-dependent Hemachromatosis
• Thalassemia Major
• Sickle Cell Disease

Intervention

• 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 Name: 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.

Study Arms

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).

Interventions:

• Drug: Deferoxamine
• Drug: Deferasirox
• Radiation: HIDA

• Publications *: Chirnomas D, Smith AL, Braunstein J, Finkelstein Y, Pereira L, Bergmann AK, Grant FD, Paley C, Shannon M, Neufeld EJ. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood. 2009 Nov 5;114(19):4009-13. doi: 10.1182/blood-2009-05-222729. Epub 2009 Sep 1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 8, 2008): 15
• Original Actual Enrollment: Same as current
• Actual Study Completion Date: November 2008
• Actual Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00749515
• Other Study ID Numbers: 07090349; NIH/NHLBI 1 K12 HL087164-01
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Ellis Neufeld, Boston Children's Hospital
• Original Responsible Party: Deborah Chirnomas, MD, Children's Hospital Boston
• Current Study Sponsor: Boston Children's Hospital
• Original Study Sponsor: Same as current
• Collaborators: Novartis

Investigators

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

• PRS Account: Boston Children's Hospital
• Verification Date: June 2019