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

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes (MDS); Acute Lymphoblastic Leukaemias (ALL); Acute Myeloid Leukaemias (AML); Juvenile Myelomonocytic Leukaemias (JMML)
• Intervention / Treatment: Drug: Treosulfan

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • St. Anna Children Hospital
• Czechia
  • Prague, Czechia, 150-06
    • University Hospital Motol, Charles University, Prague
• Germany
  • Düsseldorf, Germany, 40225
    • University Clinic Düsseldorf
  • Erlangen, Germany, 91054
    • University Clinic Erlangen-Nürnberg
  • Essen, Germany, 45147
    • Universitatsklinikum Essen
  • Frankfurt, Germany, 60590
    • University Hospital Johann Wolfgang Goethe
  • Hamburg, Germany, 20246
    • University Clinic Hamburg-Eppendorf
  • Hannover, Germany, 30625
    • Medical University Hannover
  • Heidelberg, Germany, 69120
    • University Clinic Heidelberg
  • Jena, Germany, 07740
    • University Clinic Jena
  • München, Germany, 80804
    • University Clinic München
  • Münster, Germany, 48129
    • University Clinic Münster
  • Regensburg, Germany, 93053
    • University Clinic Regensburg
  • Ulm, Germany, 89075
    • University Clinic Ulm
  • Würzburg, Germany, 97080
    • University Clinic Würzburg
• Italy
  • Rome, Italy, 00165
    • Ospedale Bambino Gesu Roma
  • Turin, Italy, 10126
    • Ospedale Infantile Regina Margherita Torino
• Poland
  • Bydgoszcz, Poland, 85-094
    • Bydgoszcz Medical University
  • Kraków, Poland, 30-663
    • Kraków Medical University
  • Lublin, Poland, 20-093
    • Lublin Medical University
  • Wroclaw, Poland, 50-368
    • Wroclaw Medical University
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital
  • Manchester, United Kingdom, M13 9WL
    • Central Manchester University Hospital
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treosulfan; 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; 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.; Other Names: Treograft®; Ovastat®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Engraftment after HSCT	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	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	based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03	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	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.	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)	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.	after 12 months after HSCT and until the end of the longer-term follow-up phase
Incidence and severity of acute (until day +100) and chronic (until 12 months after HSCT) graft versus host disease (aGvHD/cGvHD)	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.	until 12 months after HSCT
Use of rescue therapies including donor-lymphocyte infusions (DLIs) and further conditioning regimens		until 12 months after HSCT
PK parameters of Treosulfan and its epoxides	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).	day -6 prior to HSCT

Collaborators and Investigators

• Sponsor: medac GmbH
• Collaborators: Syneos Health; Celerion
• Investigators: Principal Investigator: Ajay Vora, MD, Prof., Great Ormond Street Hospital NHS Trust

Publications and helpful links

General Publications

• 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.

Helpful Links

• Sponsor's homepage

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2014
• Primary Completion (Actual): December 24, 2016
• Study Completion (Actual): September 30, 2019

Study Registration Dates

• First Submitted: December 22, 2014
• First Submitted That Met QC Criteria: January 6, 2015
• First Posted (Estimate): January 7, 2015

Study Record Updates

• Last Update Posted (Actual): May 4, 2020
• Last Update Submitted That Met QC Criteria: April 30, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: AML; ALL; MDS; JMML
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Lymphoid; Leukemia, Myeloid; Myelodysplastic Syndromes; Hematologic Neoplasms; Leukemia; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Juvenile; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Treosulfan
• Other Study ID Numbers: MC-FludT.17/M