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Trial record 1 of 2 for:    NCT01949129
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Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia

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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

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.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukaemia Drug: VP16 Radiation: TBI Drug: Thiotepa Drug: Treosulfan Drug: Fludarabine Drug: Busulfan Drug: ATG Thymoglobulin Drug: Cyclophosphamide Drug: Grafalon Phase 2 Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia
Study Start Date : April 2013
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : April 2026


Arm Intervention/treatment
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.

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: ATG Thymoglobulin
MD: ATG Thymo: 2,5mg/kg BW/d 3 days.
Other Name: ATG Thymo

Drug: Grafalon
MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days
Other Name: Anti-human T-lymphocyte immunoglobulin

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.

Drug: VP16
60 mg/kg BW,1 day
Other Name: Etoposide

Radiation: TBI
2 x 2Gy/day , 3 days (total 12Gy)

Drug: ATG Thymoglobulin
MD: ATG Thymo: 2,5mg/kg BW/d 3 days.
Other Name: ATG Thymo

Drug: Grafalon
MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days
Other Name: Anti-human T-lymphocyte immunoglobulin

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.

Drug: Thiotepa
2x5 mg/kg BW, 1 day
Other Name: Thio

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




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.


Other Outcome Measures:
  1. 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

  2. Secondary malignancies [ Time Frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years ]
    Incidence, type and timepoint of occurence

  3. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01949129


Contacts
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Contact: Christina Peters, Prof. MD PhD +43140170 ext 3106 christina.peters@stanna.at
Contact: Barbara Kristufek +43140470 ext 4795 barbara.kristufek@ccri.at

  Show 119 Study Locations
Sponsors and Collaborators
St. Anna Kinderkrebsforschung
ALL SCTped Forum
Investigators
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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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Prof. Christina Peters, Univ.-Prof. Dr. Christina Peters, St. Anna Kinderkrebsforschung
ClinicalTrials.gov Identifier: NCT01949129     History of Changes
Other Study ID Numbers: ALL SCTped FORUM 2012
First Posted: September 24, 2013    Key Record Dates
Last Update Posted: June 28, 2019
Last Verified: June 2019
Keywords provided by Prof. Christina Peters, St. Anna Kinderkrebsforschung:
stem cell transplantation
children and adolescents
high risk acute lymphoblastic leukaemia
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Busulfan
Thiotepa
Treosulfan
Fludarabine
Fludarabine phosphate
Etoposide
Thymoglobulin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors