Pharmacokinetics of Asparaginase and Antibody Formation in Interfant-06

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2010 by Aarhus University Hospital
Sponsor:
Information provided by:
Aarhus University Hospital
ClinicalTrials.gov Identifier:
NCT01025804
First received: December 2, 2009
Last updated: March 19, 2010
Last verified: March 2010
  Purpose

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.


Condition
Leukemia

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Post-marketing Surveillance Study of the Pharmacokinetics of Asparaginase and Antibody Formation in Interfant-06

Resource links provided by NLM:


Further study details as provided by Aarhus University Hospital:

Primary Outcome Measures:
  • pharmacokinetics, antibody formation, side effects [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples Without DNA

Serum is retained for measurement of enzyme activities and antibodies


Estimated Enrollment: 15
Study Start Date: December 2009
Estimated Study Completion Date: December 2015
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)

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
  Eligibility

Ages Eligible for Study:   up to 1 Year
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01025804

Contacts
Contact: Birgitte K Albertsen, MD +45 8949 6841 biralber@rm.dk

Locations
Denmark
Aarhus University Hospital, Department of Pediatrics Skejby Hospital Recruiting
Aarhus, Aarhus N, Denmark, 8200
Contact: Birgitte K Albertsen, MD    +45 8949 6841    biralber@rm.dk   
Principal Investigator: Birgitte K Albertsen, MD         
Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Birgitte Lausen, MD    +45 3545 8177    Birgitte.Lausen@rh.regionh.dk   
Principal Investigator: Birgitte Lausen, MD         
Finland
Helsinki University Hospital Recruiting
Helsinki, Finland
Contact: Kirsi Juhnukainen, MD    +358 2 3130000    kirsi.jahnukainen@ki.se   
Principal Investigator: Kirsi Juhnukainen, MD         
Iceland
University Hospital Reykjavik Recruiting
Reykjavik, Iceland
Contact: Jon Kristinsson, MD       jonkr@landspitali.is   
Principal Investigator: Jon Kristinsson, md         
Norway
Rikshospitalet Recruiting
Oslo, Norway
Contact: Bem Zeller, MD    +47 23069953    bem.zeller@rikshospitalet.no   
Principal Investigator: Bem Zeller, MD         
Sweden
Karolinska Recruiting
Stockholm, Sweden
Contact: Stefan Söderhäll, MD    +46 8 51774714    stefan.soderhall@karolinska.se   
Principal Investigator: Stefan Söderhäll, MD         
Sponsors and Collaborators
Aarhus University Hospital
Investigators
Study Chair: Birgitte K Albertsen, MD
  More Information

No publications provided

Responsible Party: Birgitte Klug Albertsen, M.D., Aarhus University Hospital, Skejby Hospital
ClinicalTrials.gov Identifier: NCT01025804     History of Changes
Other Study ID Numbers: Interfant-06, NOPHO, register identifier
Study First Received: December 2, 2009
Last Updated: March 19, 2010
Health Authority: Denmark: Danish Medicines Agency

Keywords provided by Aarhus University Hospital:
Interfant-06
Infant ALL
Asparaginase
Pharmacokinetics of asparaginase
Antibody formation

Additional relevant MeSH terms:
Antibodies
Asparaginase
Antineoplastic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014