Clinical trial NCT02333058: Treosulfan-based Conditioning in Paediatric Patients With Haematological Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukaemias (ALL)
Acute Myeloid Leukaemias (AML)
Myelodysplastic Syndromes (MDS)
Juvenile Myelomonocytic Leukaemias (JMML)
Keywords: ALL
AML
MDS
JMML
Lead sponsor: medac GmbH
Sponsor class: INDUSTRY
Collaborators: name: Celerion
name: Syneos Health
First posted: 2015-01-07
Enrollment: 70
Sex: ALL
Minimum age (years): 28
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Haematological malignant disease i.e. ALL, AML, MDS or JMML, indicated for allo-HSCT.
2. Indication for first allo-HSCT or second allo-HSCT due to disease relapse, graft failure, or secondary malignancy after previous HSCT.
3. 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 9/10 or 10/10 allele match after four digit typing in human leucocyte antigens (HLA)-A, B, C, DRB1 and DQB1.
4. Patients with ALL or AML in complete morphologic remission (blast counts \<5 % in BM) and patients with MDS or JMML with blast counts \< 20 % in BM at study entry.
5. Age at time of registration from 28 days to less than 18 years of age.
6. Lansky (patients aged \<16 years) or Karnofsky (patients aged ≥ 16 years) performance score of at least 70 %.
7. Written informed consent of the parents/ legal guardians and patient's assent/consent according to national regulations.
8. Females of child-bearing potential or male patients' partners with child-bearing potential must use a highly effective method of contraception (pearl index \< 1 %) such as complete sexual abstinence, combined oral contraceptive, hormone intrauterine contraceptive device (IUCD), vaginal hormone ring, transdermal contraceptive patch, contraceptive implant or depot contraceptive injection in combination with a second method of contraception like a condom or a cervical cap / diaphragm with spermicide or surgical sterilisation (vasectomy) in male patients or male partners during the study and at least 6 months thereafter.
9. Negative pregnancy test for females of child-bearing potential.

Exclusion Criteria:

1. Third or later allo-HSCT.
2. HSCT from haploidentical or umbilical cord blood donor.
3. Symptomatic involvement of central nervous system (CNS) at study entry.
4. Treatment with cytotoxic drugs within 10 days prior to day 7.
5. Obese paediatric patients with body mass index: weight (kg)/\[height (m)\]² \> 30 kg/m².
6. Solid tumours (e.g. neuroblastoma, peripheral neuroectodermal tumour \[PNET\], Ewing sarcoma).
7. Fanconi anaemia and other deoxyribonucleic acid (DNA) breakage repair disorders.
8. Impaired liver function indicated by Bilirubin \> three times the upper limit of normal (ULN) or aspartate aminotransferase/alanine aminotransferase (AST/ALT) \> five times ULN, or active infectious hepatitis.
9. Impaired renal function indicated by estimated glomerular filtration rate (\[GFR\], according to the Schwartz formula) \< 60 mL/min/1,73m2.
10. Impaired cardiac function: severe cardiac insufficiency indicated by left ventricle ejection fraction (LVEF) \< 35 %.
11. Requirement for supplementary continuous oxygen.
12. Severe active infection requiring deferral of conditioning.
13. Human immunodeficiency virus (HIV) positivity.
14. Known pregnancy, breast feeding.
15. Known hypersensitivity to Treosulfan and/or Fludarabine.

Primary outcomes:
measure: Freedom from transplant (treatment)-related mortality (TRM)
timeFrame: from the day of first administration of study medication until day +100 after HSCT
Secondary outcomes:
measure: Engraftment after HSCT
timeFrame: until engraftment
measure: Safety including early toxicity until day +100 after HSCT, serious adverse reactions (SARs) until the end of the longer-term follow-up phase
timeFrame: until 12 months after HSCT
measure: Hepatic sinusoidal obstruction syndrome (HSOS), lung toxicity (CTCAE term pulmonary fibrosis), hepatic toxicity and infections of any CTCAE grade (non-serious and serious)
timeFrame: until day +100 after HSCT
measure: Donor-type chimerism
timeFrame: on day +28, day +100 and 12 months after HSCT
measure: Non relapse mortality (NRM), transplant related mortality (TRM), graft failure rate, incidence of relapse/progression, relapse-free/progression-free survival (RFS/PFS) and overall survival (OS)
timeFrame: after 12 months after HSCT and until the end of the longer-term follow-up phase
measure: Incidence and severity of acute (until day +100) and chronic (until 12 months after HSCT) graft versus host disease (aGvHD/cGvHD)
timeFrame: until 12 months after HSCT
measure: Use of rescue therapies including donor-lymphocyte infusions (DLIs) and further conditioning regimens
timeFrame: until 12 months after HSCT
measure: PK parameters of Treosulfan and its epoxides
timeFrame: day -6 prior to HSCT
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: St. Anna Children Hospital
city: Prague
country: Czechia
facility: University Hospital Motol, Charles University, Prague
city: Düsseldorf
country: Germany
facility: University Clinic Düsseldorf
city: Erlangen
country: Germany
facility: University Clinic Erlangen-Nürnberg
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: University Hospital Johann Wolfgang Goethe
city: Hamburg
country: Germany
facility: University Clinic Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medical University Hannover
city: Heidelberg
country: Germany
facility: University Clinic Heidelberg
city: Jena
country: Germany
facility: University Clinic Jena
city: München
country: Germany
facility: University Clinic München
city: Münster
country: Germany
facility: University Clinic Münster
city: Regensburg
country: Germany
facility: University Clinic Regensburg
city: Ulm
country: Germany
facility: University Clinic Ulm
city: Würzburg
country: Germany
facility: University Clinic Würzburg
city: Rome
country: Italy
facility: Ospedale Bambino Gesu Roma
city: Turin
country: Italy
facility: Ospedale Infantile Regina Margherita Torino
city: Bydgoszcz
country: Poland
facility: Bydgoszcz Medical University
city: Kraków
country: Poland
facility: Kraków Medical University
city: Lublin
country: Poland
facility: Lublin Medical University
city: Wroclaw
country: Poland
facility: Wroclaw Medical University
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital
Study officials:
affiliation: Great Ormond Street Hospital NHS Trust
name: Ajay Vora, MD, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kalwak K, Mielcarek M, Patrick K, Styczynski J, Bader P, Corbacioglu S, Burkhardt B, Sykora KW, Drabko K, Gozdzik J, Fagioli F, Greil J, Gruhn B, Beier R, Locatelli F, Muller I, Schlegel PG, Sedlacek P, Stachel KD, Hemmelmann C, Moller AK, Baumgart J, Vora A. Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies. Bone Marrow Transplant. 2020 Oct;55(10):1996-2007. doi: 10.1038/s41409-020-0869-6. Epub 2020 Mar 20.