Pharmacokinetics of Asparaginase and Antibody Formation in Interfant-06

March 3, 2016 updated by: Birgitte Klug Albertsen, Aarhus University Hospital

Post-marketing Surveillance Study of the Pharmacokinetics of Asparaginase and Antibody Formation in Interfant-06

Asparaginase is an important drug in the treatment of childhood leukemia including in infant (<1 year). The prognosis for infants is bad.

Information about drug metabolism in neonates and infants is scarce as well as the reactions of an immature immune system to foreign proteins. The aims of this study is to describe the metabolism (pharmacokinetics) of asparaginase after administration intramuscularly and to evaluate the formation of antibodies against the drug (enzyme) during treatment in order to optimize the asparaginase treatment in infants in the future.

Study Overview

Status

Completed

Conditions

Detailed Description

Combination chemotherapy for acute lymphoblastic leukaemia (ALL) usually includes a bacterial L-asparaginase enzyme derived from Escherichia coli or Erwinia species. Several studies have described the pharmacokinetics in children above 1 year of age of asparaginase given intramuscularly as well as intravenously. The development of anti-asparaginase antibodies to these foreign proteins has also been described.

Chemotherapy for infant ALL also includes L-asparaginase. However, the pharmacokinetics of asparaginase and antibody formation in infants is needed to be described to optimize therapy for this group of patients who have a doubtful prognosis.

Background In general the information about drug metabolism in neonates and infants is scarce as well as the reactions of an immature immune system to foreign proteins. Several pharmacokinetic studies have been performed in children above one year of age, but no data is available about pharmacokinetics and antibody formation during treatment with any asparaginase preparation in infants.

Pharmacokinetics:

Asparaginase is used in the treatment of childhood ALL since it depletes the blood of asparagines, which can be synthesized by normal cells but not by leukemic lymphoblasts. It has been shown that serum activities above 100 IU/l ensure depletion of asparagine in serum and CNS. In many cases even values considerably lower than 100 IU/l will deplete asparagine from the serum1-5.

In the Interfant-06 protocol the doses of asparaginase are adopted from childhood ALL-protocols without scientific foundation. Infants may metabolise asparaginase differently and thus may not achieve amino acid depletion.

Antibody formation:

Asparaginase is a foreign protein for the human body, so patients may develop antibodies against it, resulting in allergic reactions (probably mediated by IgE-antibodies) or silent antibodies (IgG antibodies, blocking the effect of the enzyme). In the first case treatment most often is stopped and in the second case treatment is insufficient6-7, and thus giving the patient a poorer prognosis in both cases.

In Interfant-06 patients are treated with native E.coli asparaginase for a period followed by PEG-asparaginase later during their treatment. Studies in older children have shown that approximately 1/3 of the patients develop IgG-antibodies against native E.coli after 5-6 doses7. Other studies have shown that IgG-antibodies against native E.coli asparaginase cross-react with PEG-asparaginase, resulting in a faster clearance of the enzyme8. Allergic reactions (any grade) to native E.coli asparaginase are encountered in approximately 30 % of children11-12. There is no knowledge about the frequency of antibody formation during asparaginase therapy in infants.

Aim

The study has the purposes:

  • to describe the pharmacokinetics of intramuscular native E.coli and PEG-asparaginase in children below 1 year at diagnosis
  • to evaluate antibody formation during asparaginase treatment with E.coli followed by PEG-asparaginase in infants

Study Type

Observational

Enrollment (Actual)

15

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2100
        • Rigshospitalet
    • Aarhus N
      • Aarhus, Aarhus N, Denmark, 8200
        • Aarhus University Hospital, Department of Pediatrics Skejby Hospital
  • Finland
      • Helsinki, Finland
        • Helsinki University Hospital
  • Iceland
      • Reykjavik, Iceland
        • University Hospital Reykjavik
  • Norway
      • Oslo, Norway
        • Rikshospitalet
  • Sweden
      • Stockholm, Sweden
        • Karolinska

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 hour to 1 year (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Infants (children < 1 year) with ALL treated according to Interfant-06 at one of the Pediatric Oncology Centers in the Nordic Countries

Description

Inclusion Criteria:

  • infants <1 year at diagnosis
  • diagnosed with ALL
  • treated according to the international Interfant-06 protocol
  • treated at one of the pediatric oncological centers in the Nordic countries

Exclusion Criteria:

  • children >1 year at diagnosis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Infants

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
pharmacokinetics, antibody formation, side effects
Time Frame: 1 year
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Aarhus University Hospital

Investigators

  • Study Chair: Birgitte K Albertsen, MD

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2009

Primary Completion (Actual)

December 1, 2014

Study Completion (Actual)

December 1, 2015

Study Registration Dates

First Submitted

December 2, 2009

First Submitted That Met QC Criteria

December 3, 2009

First Posted (Estimate)

December 4, 2009

Study Record Updates

Last Update Posted (Estimate)

March 4, 2016

Last Update Submitted That Met QC Criteria

March 3, 2016

Last Verified

March 1, 2016

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • Interfant-06, NOPHO
  • register identifier (Registry Identifier: NOPHO)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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