Treosulfan Pharmacokinetics in Children Undergoing Allogeneic HSCT

Study Overview
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Brief Summary
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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).

Official Title
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Evaluation of Treosulfan Pharmacokinetics (PK) in Children Undergoing Allogeneic Haematopoietic Stem Cell Transplantation (HSCT)

Conditions
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Allogeneic Haematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Drug: Treosulfan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥ 28 days and ≤ 18 years old; Karnofsky Performance Status ≥ 50 or Lansky Performance Status ≥ 30; provide signed, written informed consent from parent or guardian; be able to comply with study procedures and follow-up examinations; have adequate organ function (as indicated by Table 1, page 27), within 14 days prior enrollment; negative pregnancy test in post-pubertal female patients. Exclusion Criteria: patients aged < 28 days and > 18 years old; patients with compromised organ function*; patients with any other severe concurrent disease, which, in the judgment of the Investigator, would make the patient inappropriate for entry into this study; known hypersensitivity to Treosulfan or Fludarabine; pregnancy/lactation.

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Treosulfan PK<br>Children with indication to HSCT receiving Treosulfan | Drug: Treosulfan<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1) Assess interindividual and intraindividual variability of PK parameters in children of different age and weight; | 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. | day -7 and -5 pre HSCT | 
| 2) Assess the relationship between PK parameters and patient characteristics; | 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). | day -7 and -5 pre HSCT | 
| 3) Assess the relationship between Treosulfan PK and regimen related toxicity (using the NCI toxicity criteria scoring system) and survival; | 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 | from day -7 pre HSCT to day +100 post HSCT | 
| 4) Assess the relationship between Treosulfan PK and efficacy parameters, such as rate of engraftment and donor chimerism. | 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. | from day -7 pre HSCT to day + 360 post HSCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treosulfan pharmacokinetics, Children, Any condition that requires an allogeneic HSCT