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Treosulfan-based Conditioning in Paediatric Patients With Haematological Malignancies

Primary Purpose

Acute Lymphoblastic Leukaemias (ALL), Acute Myeloid Leukaemias (AML), Myelodysplastic Syndromes (MDS)

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Treosulfan
Sponsored by
medac GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukaemias (ALL) focused on measuring ALL, AML, MDS, JMML

Eligibility Criteria

28 Days - 17 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • St. Anna Children Hospital
  • University Hospital Motol, Charles University, Prague
  • University Clinic Düsseldorf
  • University Clinic Erlangen-Nürnberg
  • Universitätsklinikum Essen
  • University Hospital Johann Wolfgang Goethe
  • University Clinic Hamburg-Eppendorf
  • Medical University Hannover
  • University Clinic Heidelberg
  • University Clinic Jena
  • University Clinic München
  • University Clinic Münster
  • University Clinic Regensburg
  • University Clinic Ulm
  • University Clinic Würzburg
  • Ospedale Bambino Gesu Roma
  • Ospedale Infantile Regina Margherita Torino
  • Bydgoszcz Medical University
  • Kraków Medical University
  • Lublin Medical University
  • Wroclaw Medical University
  • Birmingham Children's Hospital
  • Central Manchester University Hospital
  • Sheffield Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treosulfan

Arm Description

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.

Outcomes

Primary Outcome Measures

Freedom from transplant (treatment)-related mortality (TRM)
TRM is defined as death from any transplant-related cause

Secondary Outcome Measures

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
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
Hepatic sinusoidal obstruction syndrome (HSOS), lung toxicity (CTCAE term pulmonary fibrosis), hepatic toxicity and infections of any CTCAE grade (non-serious and serious)
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.
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.
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.
Use of rescue therapies including donor-lymphocyte infusions (DLIs) and further conditioning regimens
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).

Full Information

First Posted
December 22, 2014
Last Updated
April 30, 2020
Sponsor
medac GmbH
Collaborators
Celerion, Syneos Health
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1. Study Identification

Unique Protocol Identification Number
NCT02333058
Brief Title
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

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Completed
Study Start Date
November 21, 2014 (Actual)
Primary Completion Date
December 24, 2016 (Actual)
Study Completion Date
September 30, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
medac GmbH
Collaborators
Celerion, Syneos Health

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukaemias (ALL), Acute Myeloid Leukaemias (AML), Myelodysplastic Syndromes (MDS), Juvenile Myelomonocytic Leukaemias (JMML)
Keywords
ALL, AML, MDS, JMML

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
70 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treosulfan
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Treosulfan
Other Intervention Name(s)
Treograft®, Ovastat®
Intervention Description
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.
Primary Outcome Measure Information:
Title
Freedom from transplant (treatment)-related mortality (TRM)
Description
TRM is defined as death from any transplant-related cause
Time Frame
from the day of first administration of study medication until day +100 after HSCT
Secondary Outcome Measure Information:
Title
Engraftment after HSCT
Description
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
Time Frame
until engraftment
Title
Safety including early toxicity until day +100 after HSCT, serious adverse reactions (SARs) until the end of the longer-term follow-up phase
Description
based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time Frame
until 12 months after HSCT
Title
Hepatic sinusoidal obstruction syndrome (HSOS), lung toxicity (CTCAE term pulmonary fibrosis), hepatic toxicity and infections of any CTCAE grade (non-serious and serious)
Time Frame
until day +100 after HSCT
Title
Donor-type chimerism
Description
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.
Time Frame
on day +28, day +100 and 12 months after HSCT
Title
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)
Description
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.
Time Frame
after 12 months after HSCT and until the end of the longer-term follow-up phase
Title
Incidence and severity of acute (until day +100) and chronic (until 12 months after HSCT) graft versus host disease (aGvHD/cGvHD)
Description
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.
Time Frame
until 12 months after HSCT
Title
Use of rescue therapies including donor-lymphocyte infusions (DLIs) and further conditioning regimens
Time Frame
until 12 months after HSCT
Title
PK parameters of Treosulfan and its epoxides
Description
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).
Time Frame
day -6 prior to HSCT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
28 Days
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ajay Vora, MD, Prof.
Organizational Affiliation
Great Ormond Street Hospital NHS Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Anna Children Hospital
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
University Hospital Motol, Charles University, Prague
City
Prague
ZIP/Postal Code
150-06
Country
Czechia
Facility Name
University Clinic Düsseldorf
City
Düsseldorf
ZIP/Postal Code
40225
Country
Germany
Facility Name
University Clinic Erlangen-Nürnberg
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
Universitätsklinikum Essen
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
University Hospital Johann Wolfgang Goethe
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
University Clinic Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Medical University Hannover
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
University Clinic Heidelberg
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
University Clinic Jena
City
Jena
ZIP/Postal Code
07740
Country
Germany
Facility Name
University Clinic München
City
München
ZIP/Postal Code
80804
Country
Germany
Facility Name
University Clinic Münster
City
Münster
ZIP/Postal Code
48129
Country
Germany
Facility Name
University Clinic Regensburg
City
Regensburg
ZIP/Postal Code
93053
Country
Germany
Facility Name
University Clinic Ulm
City
Ulm
ZIP/Postal Code
89075
Country
Germany
Facility Name
University Clinic Würzburg
City
Würzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Ospedale Bambino Gesu Roma
City
Rome
ZIP/Postal Code
00165
Country
Italy
Facility Name
Ospedale Infantile Regina Margherita Torino
City
Turin
ZIP/Postal Code
10126
Country
Italy
Facility Name
Bydgoszcz Medical University
City
Bydgoszcz
ZIP/Postal Code
85-094
Country
Poland
Facility Name
Kraków Medical University
City
Kraków
ZIP/Postal Code
30-663
Country
Poland
Facility Name
Lublin Medical University
City
Lublin
ZIP/Postal Code
20-093
Country
Poland
Facility Name
Wroclaw Medical University
City
Wroclaw
ZIP/Postal Code
50-368
Country
Poland
Facility Name
Birmingham Children's Hospital
City
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom
Facility Name
Central Manchester University Hospital
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom
Facility Name
Sheffield Children's Hospital
City
Sheffield
ZIP/Postal Code
S10 2TH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
32203268
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.
Results Reference
derived
Links:
URL
http://www.medac.de
Description
sponsor's homepage

Learn more about this trial

Treosulfan-based Conditioning in Paediatric Patients With Haematological Malignancies

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