Treosulfan-based Conditioning in Paediatric Patients With Haematological Malignancies

NCT02333058 | Completed Phase 2 DMC

• 1 other identifier: MC-FludT.17/M
• Study Type: interventional
• Target: 70
• Locations: 6 countries
• Sites: 24

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.

Conditions

Acute Lymphoblastic Leukaemias (ALL); Acute Myeloid Leukaemias (AML); Myelodysplastic Syndromes (MDS); Juvenile Myelomonocytic Leukaemias (JMML)

Keywords

ALL; AML; MDS; JMML

Outcome Measures

Primary Outcomes (1)

• Freedom from transplant (treatment)-related mortality (TRM)

  TRM is defined as death from any transplant-related cause

  from the day of first administration of study medication until day +100 after HSCT

Secondary Outcomes (8)

• Engraftment after HSCT

  until engraftment

• Safety including early toxicity until day +100 after HSCT, serious adverse reactions (SARs) until the end of the longer-term follow-up phase

  until 12 months after HSCT

• Hepatic sinusoidal obstruction syndrome (HSOS), lung toxicity (CTCAE term pulmonary fibrosis), hepatic toxicity and infections of any CTCAE grade (non-serious and serious)

  until day +100 after HSCT

• Donor-type chimerism

  on day +28, day +100 and 12 months after HSCT

• 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)

  after 12 months after HSCT and until the end of the longer-term follow-up phase

Study Arms (1)

Treosulfan

EXPERIMENTAL

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.

Drug: Treosulfan

Interventions

Treosulfan DRUG

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.

Also known as: Treograft®, Ovastat®

Treosulfan

Eligibility Criteria

• Age: 28 Days - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Haematological malignant disease i.e. ALL, AML, MDS or JMML, indicated for allo-HSCT.
• Indication for first allo-HSCT or second allo-HSCT due to disease relapse, graft failure, or secondary malignancy after previous 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 9/10 or 10/10 allele match after four digit typing in human leucocyte antigens (HLA)-A, B, C, DRB1 and DQB1.
• 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.
• Age at time of registration from 28 days to less than 18 years of age.
• Lansky (patients aged \<16 years) or Karnofsky (patients aged ≥ 16 years) performance score of at least 70 %.
• Written informed consent of the parents/ legal guardians and patient's assent/consent according to national regulations.
• 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.
• Negative pregnancy test for females of child-bearing potential.

You may not qualify if:

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

Sponsors & Collaborators

• medac GmbH: lead
• Celerion: collaborator
• Syneos Health: collaborator

Study Sites (24)

St. Anna Children Hospital

Vienna, A-1090, Austria

Location

University Hospital Motol, Charles University, Prague

Prague, 150-06, Czechia

Location

University Clinic Düsseldorf

Düsseldorf, 40225, Germany

Location

University Clinic Erlangen-Nürnberg

Erlangen, 91054, Germany

Location

Universitätsklinikum Essen

Essen, 45147, Germany

Location

University Hospital Johann Wolfgang Goethe

Frankfurt, 60590, Germany

Location

University Clinic Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Medical University Hannover

Hanover, 30625, Germany

Location

University Clinic Heidelberg

Heidelberg, 69120, Germany

Location

University Clinic Jena

Jena, 07740, Germany

Location

University Clinic München

München, 80804, Germany

Location

University Clinic Münster

Münster, 48129, Germany

Location

University Clinic Regensburg

Regensburg, 93053, Germany

Location

University Clinic Ulm

Ulm, 89075, Germany

Location

University Clinic Würzburg

Würzburg, 97080, Germany

Location

Ospedale Bambino Gesu Roma

Rome, 00165, Italy

Location

Ospedale Infantile Regina Margherita Torino

Turin, 10126, Italy

Location

Bydgoszcz Medical University

Bydgoszcz, 85-094, Poland

Location

Kraków Medical University

Krakow, 30-663, Poland

Location

Lublin Medical University

Lublin, 20-093, Poland

Location

Wroclaw Medical University

Wroclaw, 50-368, Poland

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

Central Manchester University Hospital

Manchester, M13 9WL, United Kingdom

Location

Sheffield Children's Hospital

Sheffield, S10 2TH, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 32203268 DERIVED

Related Links

• sponsor's homepage

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

treosulfan

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Ajay Vora, MD, Prof.

  Great Ormond Street Hospital NHS Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2014
• First Posted: January 7, 2015
• Study Start: November 21, 2014
• Primary Completion: December 24, 2016
• Study Completion: September 30, 2019
• Last Updated: May 4, 2020

Record last verified: 2020-04

Locations

CZ (1); GB (3); IT (2); PL (4); DE (13); AU (1)