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Treosulfan Pharmacokinetics in Children Undergoing Allogeneic HSCT (TreoPK)

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ClinicalTrials.gov Identifier: NCT02048800
Recruitment Status : Unknown
Verified October 2016 by Great Ormond Street Hospital for Children NHS Foundation Trust.
Recruitment status was:  Recruiting
First Posted : January 29, 2014
Last Update Posted : October 19, 2016
Sponsor:
Collaborator:
Newcastle-upon-Tyne Hospitals NHS Trust
Information provided by (Responsible Party):
Great Ormond Street Hospital for Children NHS Foundation Trust

Brief Summary:

Every year around 70 children affected by cancer or life-threatening genetic diseases undergo haematopoietic cell transplantation (HCT) within the Blood and Marrow Transplant (BMT) unit at Great Ormond Street Hospital (GOSH).

One of the main goals of the BMT unit over the last decade has been to reduce the morbidity and mortality related to HCT, and the group has become a world-leader in pioneering less toxic transplants.

Fixed high doses of chemotherapy drugs are generally used to prepare children for HCT but several studies have shown a correlation between the concentration of these drugs achieved in the patient's blood, and the success or failure of the HCT procedure.

Recently a new drug, Treosulfan, has become available for use in patients undergoing HCT, and GOSH has pioneered its introduction in children undergoing HCT. With promising early results, Treosulfan has become the pre-HCT drug of choice, however, very little is currently known about how the drug is metabolised and cleared from the body, particularly in children.

The investigators therefore plan to investigate the pharmacokinetic (PK) profile of Treosulfan in children undergoing HCT at GOSH and define which parameters affect its metabolism and clearance, and what blood levels are associated with a favourable outcome (graft take without toxicity) or a poor result (graft rejection and/or toxicity).


Condition or disease Intervention/treatment
Allogeneic Haematopoietic Stem Cell Transplantation Drug: Treosulfan

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Study Type : Observational
Estimated Enrollment : 90 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Evaluation of Treosulfan Pharmacokinetics (PK) in Children Undergoing Allogeneic Haematopoietic Stem Cell Transplantation (HSCT)
Study Start Date : March 2014
Estimated Primary Completion Date : March 2017
Estimated Study Completion Date : March 2017

Group/Cohort Intervention/treatment
Treosulfan PK
Children with indication to HSCT receiving Treosulfan
Drug: Treosulfan
Treosulfan will be administered over 3 days prior to HSCT at the following dose: 10 g/m2 (children aged < 3months) or 12 g/m2 (children aged 3/12 months) or 14 g/m2 (children aged > 12 months)




Primary Outcome Measures :
  1. 1) Assess maximum concentration (Cmax) after Treosulfan infusion in children prior to allogeneic haematopoietic stem cell transplantation. [ Time Frame: day -7 and day -5 pre HSCT ]
  2. 2) Assess half life after Treosulfan infusion in children prior to allogeneic haematopoietic stem cell transplantation. [ Time Frame: Day -7 and day-5 pre HSCT ]
  3. 3) Assess the area under the curve (AUC) after Treosulfan infusion in children prior to allogeneic haematopoietic stem cell transplantation. [ Time Frame: Day -7 and day -5 pre HSCT ]

Secondary Outcome Measures :
  1. 1) Assess interindividual and intraindividual variability of PK parameters in children of different age and weight; [ Time Frame: day -7 and -5 pre HSCT ]
    To measure Treosulfan PK parameteres such as maximum concentration, area under the curve and half life after the first (day -7) and third (day -5) dose of Treosulfan and study if there is any significant intrapatient and interpatient variability of these results.

  2. 2) Assess the relationship between PK parameters and patient characteristics; [ Time Frame: day -7 and -5 pre HSCT ]
    To study the relationship between treosulfan PK parameters such as area under the curve, maximum concentration and half life after the 1st and 3rd administration and pre-HSCT parameters such as renal function (creatinine, urea levels) and liver function (ALT, AST, GGT, bilirubin).

  3. 3) Assess the relationship between Treosulfan PK and regimen related toxicity (using the NCI toxicity criteria scoring system) and survival; [ Time Frame: from day -7 pre HSCT to day +100 post HSCT ]
    The toxicity of the transplant will be recorded in the clinical notes and CRF forms using the NCI toxicity criteria (toxicity score for every organ/system, with a range from 1 to 5). This information will be correlated to Treosulfan PK criteria such as maximum concentration and area under the curve

  4. 4) Assess the relationship between Treosulfan PK and efficacy parameters, such as rate of engraftment and donor chimerism. [ Time Frame: from day -7 pre HSCT to day + 360 post HSCT ]
    Donor engraftment in the peripheral blood (in different cell lineages: CD15+ cells and CD3+ cells) will be addressed regularly after HSCT and these results will be correlated with Treosulfan PK parameters such as area under the curve.


Biospecimen Retention:   Samples Without DNA
Plasma will be stored for Treosulfan PK analysis.


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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Children affected by malignant or non-malignant diseases with an indication to allogeneic HSCT.
Criteria

Inclusion Criteria:

  1. age ≥ 28 days and ≤ 18 years old;
  2. Karnofsky Performance Status ≥ 50 or Lansky Performance Status ≥ 30;
  3. provide signed, written informed consent from parent or guardian;
  4. be able to comply with study procedures and follow-up examinations;
  5. have adequate organ function (as indicated by Table 1, page 27), within 14 days prior enrollment;
  6. negative pregnancy test in post-pubertal female patients.

Exclusion Criteria:

  1. patients aged < 28 days and > 18 years old;
  2. patients with compromised organ function*;
  3. patients with any other severe concurrent disease, which, in the judgment of the Investigator, would make the patient inappropriate for entry into this study;
  4. known hypersensitivity to Treosulfan or Fludarabine;
  5. pregnancy/lactation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02048800


Contacts
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Contact: Robert Chiesa, MD 02078138434 ext 8434 robert.chiesa@gosh.nhs.uk

Locations
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United Kingdom
Great Ormond Street Hospital for Children Recruiting
London, United Kingdom, WC1N 3JH
Contact: Robert Chiesa, MD    02078138434 ext 8434    robert.chiesa@gosh.nhs.uk   
Contact: Praseeda Thaikaloor    02079052346    praseeda.thaikalloor@gosh.nhs.uk   
Great North Childrens Hospital Recruiting
Newcastle Upon Tyne, United Kingdom, NE1 4LP
Contact: Mary Slatter, MD    01912823767    mary.slatter@nuth.nhs.uk   
Sponsors and Collaborators
Great Ormond Street Hospital for Children NHS Foundation Trust
Newcastle-upon-Tyne Hospitals NHS Trust
Investigators
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Principal Investigator: Robert Chiesa, MD Great Ormond Street Hospital, London, UK
Principal Investigator: Mary Slatter, MD Great North Childrens Hospital, Newcastle upon Tyne, UK

Publications:
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Responsible Party: Great Ormond Street Hospital for Children NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02048800     History of Changes
Other Study ID Numbers: 10MI28
First Posted: January 29, 2014    Key Record Dates
Last Update Posted: October 19, 2016
Last Verified: October 2016

Keywords provided by Great Ormond Street Hospital for Children NHS Foundation Trust:
Treosulfan pharmacokinetics
Children
Any condition that requires an allogeneic HSCT

Additional relevant MeSH terms:
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Treosulfan
Busulfan
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Myeloablative Agonists