Treosulfan-based Versus Busulfan-based Conditioning in Paediatric Patients With Non-malignant Diseases

Sponsor

medac GmbH (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02349906

Collaborator

Celerion (Industry), Venn Life Sciences (Other), Syneos Health (Other)

106

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of the trial is to describe the safety and efficacy of intravenous (i.v.) Treosulfan compared to the conventional (myeloablative) dose of i.v. Busulfan, each administered as part of a standardised Fludarabine-containing conditioning regimen and to contribute to a PK model which permits - in conjunction with data comparing Treosulfan and Busulfan in adults with malignant diseases - to extend the use of Treosulfan in the paediatric population by extrapolating efficacy.

Condition or Disease	Intervention/Treatment	Phase
Primary Immunodeficiencies Inborn Errors of Metabolism Haemoglobinopathies Bone Marrow Failure Syndromes	Drug: Treosulfan Drug: Busilvex	Phase 2

Detailed Description

The prospective clinical phase II protocol MC-FludT.16/NM is to be conducted to verify safety and efficacy of Treosulfan-based conditioning compared to Busulfan-based conditioning in paediatric patients. Based on the given clinical experience with either Treosulfan-based or Busulfan-based conditioning in combination with Fludarabine no increased risk for graft failure is expected in paediatric patients. A potential benefit for study patients is expected with respect to a probably low non-haematological toxicity of treatment compared to myeloablative TBI-based conditioning or high-dose Busulfan-based conditioning in combination with Cyclophosphamide.

However, the allogeneic HSCT procedure itself potentially involves serious risks with regard to severe or life-threatening conditions like graft versus host disease (GvHD) and/or infectious complications as well as graft failure.

In summary, the primary goal of this study is to evaluate the Treosulfan-based myeloablative conditioning regimen as an alternative in children and to contribute to the current PK model for Treosulfan to be able to finally give age (or body surface area [BSA]) dependent dose recommendations. The treatment regimens given in the protocol MC-FludT.16/NM are based on sufficient clinical safety and efficacy data. Considering the vital indication for allogeneic HSCT of the selected patient population, the risk-benefit assessment seems to be in favour of the study conduct.

Moreover, planned interim analyses will ensure the early identification of unexpected risks. Therefore, the conduct of the protocol MC-FludT.16/NM is considered reasonably justified.

Study Design

Study Type:

Interventional

Actual Enrollment :

106 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Clinical Phase II Trial to Compare Treosulfan-based Conditioning Therapy With Busulfan-based Conditioning Prior to Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) in Paediatric Patients With Non-malignant Diseases

Study Start Date :

Apr 1, 2015

Actual Primary Completion Date :

May 7, 2020

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treosulfan One Treosulfan dose per day administered i.v. on three consecutive days (-6, -5 and -4); given over 2 hours as part of background conditioning prior to allogeneic stem cell transplantation. The dose has to be calculated as follows: If the BSA (m2) is equal or less than 0.3, the Treosulfan dose should be 10g/m2/day. If the BSA (m2) is greater than 0.3 and equal or less than 0.8, the Treosulfan dose should be 12g/m2/day. If the BSA (m2) is greater than 0.8, the Treosulfan dose should be 14g/m2/day.	Drug: Treosulfan
Active Comparator: Busulfan Total daily Busilvex dose (3.2 to 4.8 mg/kg/day, based on body weight) according to authorised dosage for children and adolescents administered i.v. as part of the background conditioning regimen on four consecutive days (days -7, -6, -5 and -4); given in 1, 2, or 4 portions per day according to the respective hospital's standard.	Drug: Busilvex

Arm

Intervention/Treatment

Experimental: Treosulfan

One Treosulfan dose per day administered i.v. on three consecutive days (-6, -5 and -4); given over 2 hours as part of background conditioning prior to allogeneic stem cell transplantation. The dose has to be calculated as follows: If the BSA (m2) is equal or less than 0.3, the Treosulfan dose should be 10g/m2/day. If the BSA (m2) is greater than 0.3 and equal or less than 0.8, the Treosulfan dose should be 12g/m2/day. If the BSA (m2) is greater than 0.8, the Treosulfan dose should be 14g/m2/day.

Drug: Treosulfan

Active Comparator: Busulfan

Total daily Busilvex dose (3.2 to 4.8 mg/kg/day, based on body weight) according to authorised dosage for children and adolescents administered i.v. as part of the background conditioning regimen on four consecutive days (days -7, -6, -5 and -4); given in 1, 2, or 4 portions per day according to the respective hospital's standard.

Drug: Busilvex

Outcome Measures

Primary Outcome Measures

Comparative evaluation of freedom from transplant (treatment)-related mortality (TRM), defined as death from any transplant-related cause from the day of first administration of study medication (day -7) until day +100 after HSCT. [day -7 to day +100]

Eligibility Criteria

Criteria

Ages Eligible for Study:

28 Days to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Non-malignant disease indicated for first myeloablative allogeneic HSCT, including inborn errors of metabolism, primary immunodeficiencies, haemoglobinopathies and bone marrow failure syndromes.
First allogeneic HSCT.
Available matched sibling donor (MSD), matched family donor (MFD) or matched unrelated donor (MUD). For bone marrow (BM) and peripheral blood (PB) match is defined as at least 9/10 allele matches after four digit typing in human leucocyte antigen (HLA)-A, -B, -C, -DRB1 and DQB1 antigens. For umbilical cord blood (UCB) match is defined as at least 5/6 matches after two digit typing in HLA-A and -B and four digit typing in DRB1 antigens.

Exclusion Criteria:

Second or later HSCT.
HSCT from mismatched donor (less than 9/10 BM/peripheral blood stem cells (PBSC) or less than 5/6 matched cord donor).
Preterm newborn infants (<37 weeks gestational age) and term newborn infants aged 0 - 27 days at time of registration.
Obese paediatric patients with body mass index weight (kg)/[height (m)]² > 30 kg/m².
Diagnosis of Fanconi anaemia and other chromosomal breakage disorders, radiosensitivity disorders (deoxyribonucleic acid (DNA) Ligase 4, Cernunnos- X-ray repair cross-complementing protein 4 (XRCC4) like factor (XLF), Nijmegen Breakage Syndrome (NBS)) and Dyskeratosis Congenita.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	University Hospital Motol, Dep. of Paediatric Haematology and Oncology	Prague	Czechia
2	Department of Pediatric Oncology & Hematology, Charite Berlin	Berlin	Germany	13353
3	University Children's Hospital Essen Pediatric stem cell transplantation	Essen	Germany	45122
4	University Hospital Frankfurt	Frankfurt am Main	Germany	60590
5	Hannover Medical University, Dep. of Paediatrics, Paediatric Haematology and Oncology	Hannover	Germany
6	Heidelberg University Hospital	Heidelberg	Germany	69120
7	University of Jena, Department of Pediatrics	Jena	Germany	07747
8	Ulm, University Hospital, Clinic for Children and Adolescents	Ulm	Germany	89075
9	SC Oncoematologia Pediatrica Ospedale Pediatrico Microcitemico "Antonio Cao" A.O. Brotzu	Cagliari	Italy	09121
10	UOC Ematologia ed Oncologia Pediatrica con TMO AOU Policlinico Vittorio Emanuele	Catania	Italy	95123
11	Reparto Trapianti Midollo Osseo Clinica Pediatrica Universitaria Fondazione MBBM-Ospedale San Gerardo	Monza	Italy	20900
12	S.C. Oncoematologia Pediatrica Fondazione IRCCS Policlinico San Matteo	Pavia	Italy	27100
13	Oncoematologia Pediatrica A.O. di Perugia Ospedale S. Maria della Misericordia	Perugia	Italy	06156
14	U.O. Oncoematologia Pediatrica Azienda Ospedaliero Universitaria Pisana Ospedale S. Chiara	Pisa	Italy	56100
15	Ospedale Bambino Gesu Roma	Rome	Italy	00165
16	Ospedale Infantile Regina Margherita Torino	Turin	Italy	10126
17	U.O.C. Oncoematologia Pediatrica Policlinico "G.B. Rossi" - AOUI Verona	Verona	Italy	37134
18	Szpital Uniwersytecki im. dr Antoniego Jurasza	Bydgoszcz	Poland	85-094
19	Uniwersytecki Szpital Dzieciecy w Krakowie	Krakow	Poland	30-663
20	Dzieciecy Szpital Kliniczny im. A. Gebali w Lublinie	Lublin	Poland	20-093
21	Wroclaw Medical University, Department of Pediatric Hematology/Oncology and BMT	Wroclaw	Poland	50-368