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Fludarabine

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Alkylating Agents

Treosulfan dose per day is to be calculated by using BSA. One dose of Treosulfan per day on three consecutive days (day -6, day -5 and day -4) as intravenous (i.v.) infusion, given over 2 hours.

Two background conditioning regimens with Treosulfan are allowed: One regimen consists of a standardised Fludarabine-containing regimen (regimen A) and the other consists of an intensified regimen with Fludarabine and ThioTEPA (regimen B). The investigator decides for each individual patient whether to treat the patient with regimen A or with regimen B.

Treosulfan: i.v., BSA adapted: 10, 12 or 14 g/m²/day within 120 min to be administered prior to Fludarabine; Fludarabine: i.v., 30 mg/m2/day on days from -7 to -3 prior to HSCT; ThioTEPA (Regimen B): i.v., 2 x 5mg/kg/day on day -2.

Treosulfan dose per day is to be calculated by using BSA:

One dose of Treosulfan per day on three consecutive days (day -6, day -5 and day -4) as intravenous (i.v.) infusion, given over 2 hours.

Two background conditioning regimens with Treosulfan are allowed: One regimen consists of a standardised Fludarabine-containing regimen (regimen A) and the other consists of an intensified regimen with Fludarabine and ThioTEPA (regimen B). The investigator decides for each individual patient whether to treat the patient with regimen A or with regimen B.

Treosulfan: i.v., BSA adapted: 10, 12 or 14 g/m²/day within 120 min to be administered prior to Fludarabine; Fludarabine: i.v., 30 mg/m2/day on days from -7 to -3 prior to HSCT; ThioTEPA (Regimen B): i.v., 2 x 5mg/kg/day on day -2.

Ajay Vora, MD, Prof.

The primary goal of this study is to evaluate an alternative myeloablative, but reduced toxicity conditioning regimen in children, to describe the safety and efficacy of intravenous (i.v.) Treosulfan administered as part of a standardised Fludarabine-containing conditioning and to contribute to the current pharmacokinetic model to be able to finally give age (or body surface area) dependent dose recommendations. The treatment regimens given in the protocol MC-FludT.17/M are based on sufficient clinical safety and efficacy data. Considering the vital indication for allogeneic haematopoietic stem cell transplantation of the selected patient population, the risk-benefit assessment is therefore reasonably in favour of the study conduct.

The protocol MC-FludT.17/M is a clinical phase II trial to describe the safety and efficacy of Treosulfan-based conditioning therapy prior to allogeneic haematopoietic stem cell transplantation (allo-HSCT) in at least 70 paediatric patients with haematological malignancies (male and female children with haematological malignant diseases as acute lymphoblastic leukaemias (ALL), acute myeloid leukaemias (AML), myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukaemias (JMML), requiring myeloablative conditioning treatment with following allo-HSCT).

Treosulfan dose per day is to be calculated by using body surface area (BSA). Two background conditioning regimens with Treosulfan are allowed: One regimen consists of a standardised Fludarabine-containing regimen and the other consists of an intensified regimen with Fludarabine and ThioTEPA.

Freedom from transplant (treatment)-related mortality (TRM), defined as death from any transplant-related cause from the day of first administration of study medication until day +100 after HSCT is the primary objective of the trial.

Moreover, the current pharmacokinetic (PK) model should be contributed to be able to finally give age (or BSA) dependent dose recommendations.

Treosulfan-based Conditioning in Paediatric Patients With Haematological Malignancies

Clinical Phase II Trial to Describe the Safety and Efficacy of Treosulfan-based Conditioning Therapy Prior to Allogeneic Haematopoietic Stem Cell Transplantation in Paediatric Patients With Haematological Malignancies

TRM is defined as death from any transplant-related cause

Engraftment is defined as first of three consecutive days for each of the following four criteria:

* a leukocyte count of more than 1 x 109/L
* an absolute neutrophil count (ANC) of more than 0.5 x 109/L
* a platelet count of at least 20 x 109/L in the absence of platelet transfusion
* a platelet count of at least 50 x 109/L in the absence of platelet transfusion

based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

The incidences of complete donor-type chimerism will be estimated as the number of patients with complete chimerism divided by the total number of patients at risk.

Non-relapse mortality will be defined as the probability of dying in the absence of persisting disease or previous occurrence of relapse/progression or graft failures.

TRM is defined as the probability of dying from a transplant-related cause. The associated time span is defined as the interval from day 0 to death due to a transplant-related cause.

The incidence of relapse/progression is defined as the probability of having relapse/progression of the underlying disease.

Relapse-free/progression-free survival is defined as the time length between day 0 and the date of relapse/progression of the underlying disease or death due to any cause.

OS after HSCT is defined as the probability of surviving. Survival time is defined as the time period between day 0 and the day of death due to any cause.

Kaplan-Meier methods will be applied for estimating the probability of these parameters over time.

The probability of grade I-IV and grade III-IV aGvHD will be estimated by cumulative incidence rates and summarised for selected time points together with their approximate 90 % confidence intervals.

As for aGvHD, the probability of cGvHD will be estimated by cumulative incidence rates.

The following PK parameters of Treosulfan and its epoxides will be measured: Clearance (CL); volume of distribution (Vss); terminal elimination rate constant (λz); terminal elimination half-life (t1/2); area under the concentration time curve from time zero to infinity (AUC∞); maximum observed concentration (Cmax, i.e. C end of infusion).

Celerion

Syneos Health

medac GmbH

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Treosulfan-based Conditioning in Paediatric Patients With Haematological Malignancies	NCT02333058	Acute Lymphobla... Acute Myeloid L... Myelodysplastic... Juvenile Myelom...	Treosulfan	28 Days - 17 Years	medac GmbH
Treosulfan-based Conditioning in Paediatric Patients With Haematological Malignancies	NCT02333058	Acute Lymphobla... Acute Myeloid L... Myelodysplastic... Juvenile Myelom...	Treosulfan	28 Days - 17 Years	medac GmbH

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