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Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01949129
Recruitment Status : Recruiting
First Posted : September 24, 2013
Last Update Posted : June 28, 2019
Sponsor:
Collaborator:
ALL SCTped Forum
Information provided by (Responsible Party):
Prof. Christina Peters, St. Anna Kinderkrebsforschung

Tracking Information
First Submitted Date  ICMJE September 9, 2013
First Posted Date  ICMJE September 24, 2013
Last Update Posted Date June 28, 2019
Study Start Date  ICMJE April 2013
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 26, 2019)
  • Overall Survival (OS) Stratum 1a (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    Stratum 1 - randomisation related question was closed in December 2018; patients are in active follow-up: To show that a non total body irradiation (TBI) containing conditioning (Flu/Thio/ivBu or Flu/Thio/Treo) results in a non-inferior survival as compared to conditioning with TBI/Etoposide in children older than 4 years after HSCT from a Human leucocyte antigen (HLA) identical sibling donor (MSD) or a HLA matched donor (MD). The primary endpoint is the OS calculated from the date of the randomisation. Death from any cause will be considered an event.
  • Event free survival (EFS) Stratum 2 (mismatched donor transplantation) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    EFS after allogeneic HSCT. EFS calculated from date of recruitment to disease progression or relapse, secondary neoplasm and death from any cause.
  • Overall Survival (OS), Stratum 1b: MSD/MD without randomisation [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    To explore the impact of risk factors on the incidence of adverse events of special interest (AESIs) and on overall survival and event free survival in the entire MSD/MD cohort
Original Primary Outcome Measures  ICMJE
 (submitted: September 19, 2013)
  • Overall Survival (OS) Stratum 1 (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
  • Event free survival (EFS) Stratum 2 (mismatched donor transplantation) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
Change History Complete list of historical versions of study NCT01949129 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2019)
  • EFS (Stratum 1a and 1b) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    EFS calculated from date of randomization (1a) or recruitment (1b) to disease progression or relapse, secondary neoplasm and death from any cause. Patients lost to follow-up without event will be censored at the date of their last follow-up evaluation.
  • TRM [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    Cumulative Incidence of Treatment-related mortality (TRM) for Stratum 1 and 2.
  • Relapse/progression [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    Cumulative Incidence of Relapse for Stratum 1a, 1b and 2.
  • Acute and late toxicity for Stratum 1a, 1b and 2 [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    according a preselection out of CTC3
  • OS (Stratum 2) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    The primary endpoint is the OS calculated from the date of the recruitment . Death from any cause will be considered an event.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2013)
  • EFS (Stratum 1) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
  • Cumulative Incidence of Treatment-related mortality (TRM) for Stratum 1 and 2 [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
  • Cumulative Incidence of Relapse for Stratum 1 and 2 [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
  • acute and late toxicity for Stratum 1 and 2 [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    according a preselection out of CTC3
  • OS (Stratum 2) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
Current Other Pre-specified Outcome Measures
 (submitted: June 26, 2019)
  • Acute Graft versus Host Disease (aGVHD) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    According to the modified Seattle Glucksberg criteria
  • Secondary malignancies [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    Incidence, type and timepoint of occurence
  • Chronic Graft-versus-host disease (cGvHD) [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    Chronic GVHD is diagnosed using criteria created through the NIH consensus development project
Original Other Pre-specified Outcome Measures
 (submitted: September 19, 2013)
  • Acute Graft versus Host Disease (aGVHD) according Glucksberg Scale and Seattle Criteria [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
  • Secondary malignancies [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    Incidence, type and timepoint of occurence
  • Chronic Graft-versus-host disease (cGvHD) according Glucksberg Scale and Seattle Criteria [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
 
Descriptive Information
Brief Title  ICMJE Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia
Official Title  ICMJE Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia
Brief Summary

The ALL SCTped 2012 FORUM is a multinational, multi-centre, controlled, prospective phase III study for the therapy and therapy optimisation for children and adolescents with ALL in complete morphological remission (CR, less than 5% bone marrow blasts, no blasts in cerebrospinal fluid, no other extramedullary leukemia), who have an indication for HSCT with a myeloablative conditioning regimen.

The stratification of patients in first and following remissions according to the individual transplantation modalities rests upon an indication for allogeneic HSCT and the availability of a suitable donor within the individual transplantation groups.

Detailed Description

Acute and late side effects of TBI in combination with other chemotherapeutic are manifold to the growing organism and include severe organ dysfunction/failure due to toxicity. Although transplant associated mortality was reduced after HSCT in the last decade due to better HLA matching, infection prevention and control, the burden of late complications is still a matter of concern. Growth retardation, hormonal dysfunction, sterility and the risk of secondary cancer are the late consequences of TBI in children. However, so far no prospective study has demonstrated similar outcomes in paediatric ALL using chemo-conditioning regimen before HSCT. The reason for that is manifold: only a minority of children with ALL qualifies for allogeneic HSCT as most patients are cured with sole modern chemotherapy approaches. Those with dismal prognosis are treated in HSCT centres offering a care to patients with different diseases. Therefore it is nearly impossible to answer the complex outcome questions in single centres or even in single countries. International cooperation is essential to allow prospective investigation within comparable patient cohorts.

This study aimed to explore the efficacy and efficiency of two different chemo-conditioning regimens (Flu/Thio with Treo or ivBu) in comparison to the standard conditioning regimen (TBI/VP16). All patients with an indication for HSCT, age > 4 years and a matched donor (MD) or matched sibling donor (MSD) underwent a randomisation between these two conditioning regimens. The decision if the irradiation free conditioning is Flu/Thio/Treo or Flu/Thio/ivBu was stratified by country. Patients with age < 4 years received the irradiation free conditioning. Patients with a mismatched donor were stratified according to the donor's stem cell source (cordblood, haploidentical tx or bone marrow/peripheral blood stem cells).

After an interim analysis of the randomized FORUM-trial in December 2018, which showed superior OS for TBI/Etoposide with equal outcomes for Bu or Treo-containing regimen, the randomization was suspended. The reason was less relapse incidence whereas 1-year TRM was comparable in all 3 arms. The randomization was closed in March 2019 based on the results of additional analyses confirming the superiority of TBI/VP16 over chemo-conditioning. Consequently, the TBI conditioning has remained a standard for the patients older than 4 years with a MSD/MD. Use of a conditioning other than TBI/VP16 in this age group is made at the center level based on the assessment of each individual patient.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Lymphoblastic Leukaemia
Intervention  ICMJE
  • Drug: VP16
    60 mg/kg BW,1 day
    Other Name: Etoposide
  • Radiation: TBI
    2 x 2Gy/day , 3 days (total 12Gy)
  • Drug: Thiotepa
    2x5 mg/kg BW, 1 day
    Other Name: Thio
  • Drug: Treosulfan
    14g/m² BS, 3 days
    Other Name: Treo
  • Drug: Fludarabine
    30 mg/m² BS, 5 days
    Other Name: Flu
  • Drug: Busulfan
    iV, dosage according therapeutic drug monitoring, 4 days
    Other Name: Bu
  • Drug: ATG Thymoglobulin
    MD: ATG Thymo: 2,5mg/kg BW/d 3 days.
    Other Name: ATG Thymo
  • Drug: Cyclophosphamide
    50mg/kg BW/d 2 days with Mesna
    Other Name: Cy
  • Drug: Grafalon
    MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days
    Other Name: Anti-human T-lymphocyte immunoglobulin
Study Arms  ICMJE
  • Experimental: Flu/Thio/Treo

    Fludarabine/Thiotepa/Treosulfan is for conditioning before HSCT from MSD or MD. ATG Thymo or Grafalon is used for patients who receive stem cells from unrelated donors.

    Fludarabine/Thiotepa/Treosulfan with either ATG Thymo or Grafalon is also used for HSCT from MMD with in vitro T-Cell Depletion (TCD) or with CD34+ selection.

    Fludarabine/Thiotepa/Treosulfan with Post Tx-Cyclophosphamide is used for MMD-graft without in vitro TCD.

    Interventions:
    • Drug: Thiotepa
    • Drug: Treosulfan
    • Drug: Fludarabine
    • Drug: ATG Thymoglobulin
    • Drug: Grafalon
  • Active Comparator: TBI/VP16

    TBI (Total Body Irradiation) / VP16 is used for conditioning for HSCT with MSD or MD graft with patients who are older than 48 months at the time of conditioning.

    TBI/VP16 is also used with Post TX-Cyclophosphamide for MMD-graft without in vitro T-Cell Depletion.

    TBI/VP16 with either ATG Thymo or Grafalon is used for MMD-HSCT with in vitro T-Cell Depletion or with CD34+ selection.

    Interventions:
    • Drug: VP16
    • Radiation: TBI
    • Drug: ATG Thymoglobulin
    • Drug: Grafalon
  • Experimental: Flu/Thio/ivBu

    Fludarabine/Thiotepa/iV Busulfan is used for conditioning before HSCT from MSD or MD.

    Fludarabine/Thiotepa/iBu with either ATG Thymo or Grafalon is also used for HSCT from MMD-HSCT with T-Cell Depletion (TCD) or haplo with CD34+ selection.

    Fludarabine/Thiotepa/iV Busulfan with Post Tx-Cyclophosphamide is used for MMD-graft without in vitro TCD.

    Interventions:
    • Drug: Thiotepa
    • Drug: Fludarabine
    • Drug: Busulfan
    • Drug: ATG Thymoglobulin
    • Drug: Cyclophosphamide
    • Drug: Grafalon
Publications * Choong E, Uppugunduri CRS, Marino D, Kuntzinger M, Doffey-Lazeyras F, Lo Piccolo R, Chalandon Y, Peters C, Daali Y, Ansari M. Therapeutic Drug Monitoring of Busulfan for the Management of Pediatric Patients: Cross-Validation of Methods and Long-Term Performance. Ther Drug Monit. 2018 Feb;40(1):84-92. doi: 10.1097/FTD.0000000000000468. Erratum in: Ther Drug Monit. 2018 Apr;40(2):284.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 19, 2013)
1000
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2026
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Patients with ALL (except for patients with B-ALL) who fulfil the following criteria:

  • age at diagnosis ≤ 18 years. Age at HSCT ≤ 21 years
  • indication for allogeneic HSCT
  • complete remission (CR) before HSCT
  • written consent of the parents (legal guardian) and, if necessary, the minor patient via "Informed Consent Form"
  • no pregnancy
  • no secondary malignancy
  • no previous HSCT
  • HSCT is performed in a study participating centre

Exclusion Criteria:

  • patients who do not fulfil the inclusion criteria
  • Non Hodgkin-Lymphoma
  • the whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
  • no consent is given for saving and propagation of anonymous medical data for study reasons
  • severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders)
  • Karnofsky / Lansky score < 50%
  • subjects unwilling or unable to comply with the study procedures
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Christina Peters, Prof. MD PhD +43140170 ext 3106 christina.peters@stanna.at
Contact: Barbara Kristufek +43140470 ext 4795 barbara.kristufek@ccri.at
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belarus,   Belgium,   Canada,   Chile,   Croatia,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Hungary,   Israel,   Italy,   Malaysia,   Mexico,   Netherlands,   New Zealand,   Norway,   Poland,   Romania,   Saudi Arabia,   Slovakia,   Slovenia,   Spain,   Sweden,   Switzerland,   Turkey
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT01949129
Other Study ID Numbers  ICMJE ALL SCTped FORUM 2012
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof. Christina Peters, St. Anna Kinderkrebsforschung
Study Sponsor  ICMJE St. Anna Kinderkrebsforschung
Collaborators  ICMJE ALL SCTped Forum
Investigators  ICMJE
Study Chair: Christina Peters, Prof. MD PhD St. Anna Kinderspital, Vienna, Austria
Study Chair: Peter Bader, Prof. MD PhD Klinik für Kinder- u. Jugendheilkunde III, Johann Wolfgang Goethe Universität, Frankfurt, Germany
Study Chair: Franco Locatelli, Prof. MD PhD Pediatric Hematology and Oncology IRCCS Ospedale, Rome, Italy
PRS Account St. Anna Kinderkrebsforschung
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP