Trial document




drksid header

  DRKS00005503

Trial Description

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Title

High-dose chemotherapy and autologous stem cell transplantion or consolidating conventional chemotherapy in primary CNS lymphoma – randomized phase III trial - MATRix / IELSG43 -

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Trial Acronym

MATRix / IELSG43

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URL of the Trial

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Brief Summary in Lay Language

In the multicentre Phase III trial two therapies will
be compared: after intensified induction
treatment with 4 cycles rituximab, methotrexate, cytarabine and thiotepa (MATRix) all patients with a PR or CR after the induction therapy will be randomized between first-line high-dose chemotherapy followed by a ASCT against conventional consolidating therapy with 2 cycles of R-DeVic
(Rituximab, Dexamthason, Etoposide, Ifosfamide, Carboplatin).

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Brief Summary in Scientific Language

Primary central nervous system lymphoma (PCNSL) is a highly aggressive disease with rising incidence over the past 30 years. Similar to other hematological diseases, the rationale for consolidation in PCNSL is the elimination of minimal residual disease. The efficacy of WBRT, which is the current standard for consolidation after HD-MTX-based systemic treatment, is being compared to HDT-ASCT in the ongoing IELSG-32 trial.
High-dose chemotherapy with carmustine or busulfan and thiotepa followed by autologous stem cell transplantation has been shown to be feasible and highly effective in newly diagnosed eligible patients, but also in the salvage situation.
The question we aim to answer is whether HDT-ASCT is superior to conventional therapy as consolidation after intensified immunochemotherapy in newly diagnosed PCNSL.
In the framework of the substantial amendment 01 dated May 7th, 2018 the following changes have been made: Increase of sample size from 250 to 330; prolongation of recruitment period until August 31st, 2019;
adapted inclusion criterion for randomization -> reduction of number of stemcells that need to be harvested before randomization. The Czech Repubic has withdrawn its confirmation to participate in the trial.

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Organizational Data

  •   DRKS00005503
  •   2014/04/22
  •   2015/08/24
  •   yes
  •   Approved
  •   AM-2014010-ff, Ethik-Kommission bei der Landesärztekammer Baden-Württemberg
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Secondary IDs

  •   2012-000620-17 
  •   NCT02531841  (clinicaltrials.gov)
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Health Condition or Problem studied

  •   C83.3 -  Diffuse large B-cell lymphoma
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Interventions/Observational Groups

  •   INDUCTION TREATMENT:
    4 cycles MATRix (every 3 weeks), stem-cell harvest after 2nd cycle:
    - Rituximab 375 mg/m²/d i.v. (d0,5)
    - MTX 3.5 g/m² i.v. (d1)
    - Ara-C 2 x 2 g/m²/d i.v. (d2-3)
    - Thiotepa 30 mg/m² i.v. (d4)


    CONSOLIDATION
    2 cycles of R-DeVIC (every 3 weeks):
    - Rituximab 375 mg/m²/d i.v. (d0)
    - Dexamethasone 40 mg/d i.v. (d1-3)
    - Etoposide 100 mg/m²/d i.v. (d1-3)
    - Ifosfamide 1500 mg/m²/d i.v. (d1-3)
    - Carboplatin 300 mg/m² i.v. (d1)


    Generic and proprietary name:
    Rituximab - MabT hera®
    Methotrexate - Methotrexat
    Cytarabine - ARA-cell®
    Thiotepa - TEPADINA®
    Carmustine/BCNU - CARMUBRIS®
    Busulfan - Busilvex®
    Dexamethasone - Fortecortin®
    Etosposide/VP-16 - ETOPOPHOS®
    Ifosfamide - IFO-cell®
    Carboplatine - CARBO-cell®
  •   INDUCTION TREATMENT:
    4 cycles MATRix (every 3 weeks), stem-cell harvest after 2nd cycle:
    - Rituximab 375 mg/m²/d i.v. (d0,5)
    - MTX 3.5 g/m² i.v. (d1)
    - Ara-C 2 x 2 g/m²/d i.v. (d2-3)
    - Thiotepa 30 mg/m² i.v. (d4)


    CONSOLIDATION:
    High-dose chemotherapy (HDT):
    - BCNU* 400 mg/m² i.v. (d-6)
    - Thiotepa 2 x 5 mg/kg/d i.v. (d-5-(-4))
    - ASCT (d0)

    *if not available at study site, Busulfan can be administered instead:
    - Busulfan 3,2 mg/kg/d i.v. (d-8-(-7))
    - Thiotepa 2 x 5 mg/kg/d i.v. (d-5-(-4))
    - ASCT (d0)

    Generic and proprietary name:
    Rituximab - MabT hera®
    Methotrexate - Methotrexat
    Cytarabine - ARA-cell®
    Thiotepa - TEPADINA®
    Carmustine/BCNU - CARMUBRIS®
    Busulfan - Busilvex®
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
  •   No
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Primary Outcome

Primary efficacy endpoint:
Progression-free survival (PFS) time from randomization until progression, relapse, or death from any cause.

Progression-free survival PFS:
Response Assessment III at the end of study treatment (EOT) visit and
every imaging diagnostic assessments during follow-up period:
during year 1-2: every 3 month
from year 3-5: every 6 month
or imaging in case of clinical suspicion of disease progression or relapse

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Secondary Outcome

Secondary endpoints:
Efficacy:
- Complete response (CR)
- Response duration
- Overall survival (OS)
- Quality of life (QOL): EORTC QLQ-C30.
CR will be determined on day 60 after randomization.
Response duration is defined as time from CR, CRu or PR until relapse or PD.
OS is defined as time from randomization until death of any cause.

For overall survival (OS), Quality of life (QLQ), (serious)adverse events (S)AEs, toxicity and neurotoxicity timepoints of evaluation are defined as every assessment during follow up period in accordance with the protocol.
year 1-2: every 3 month
year 3-5: every 6 month.

Response duration observation times for patients where the event of interest was not observed, will be censored at the time last seen alive without the respective event.

Safety:
- (Serious) adverse events
- Toxicity
- Neurotoxicity (MMSE, EORTC QLQ-BN20, neuropsychological test battery)



Test Battery:
ECOG Performance Status,
Mini-mental Status Examination (MMSE),
EORTC QLQ-C30,
EORTC QLQ-BN20,
Brief Repeatable Battery of Neuropsychological Tesrs

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Countries of Recruitment

  •   Germany
  •   Italy
  •   Switzerland
  •   Denmark
  •   Norway
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Locations of Recruitment

  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
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Recruitment

  •   Actual
  •   2014/07/18
  •   330
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   70   Years
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Additional Inclusion Criteria

INCLUSION CRITERIA
1. Immunocompetent patients with newly-diagnosed primary central nervous system B-cell lymphoma
2. Age 18-65 years irrespective of ECOG or 66-70 years (with ECOG Performance Status ≤ 2)
3. 3. Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist.
4. Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy
5. Disease exclusively localized in the CNS, CSF or cranial nerves
6. At least one measurable lesion
7. Previously untreated patients (previous or ongoing steroid treatment admitted)
8. Sexually active patients of childbearing potential who agree to apply adequate contraceptive measures during study participation
9. Written informed consent obtained according to international guidelines and local laws by patient or authorized legal representative in case patient is temporarily legally not competent due to his or her disease

ADDITIONAL RANDOMIZATION CRITERIA
1. Sufficient stem cell harvest (≥ 3 x 106 CD34+ cells/kg of body weight)
2. Complete remission, unconfirmed complete remission or partial remission
3. Central pathology results confirming local results
4. Exclusion criterion no. 6 not applicable for re-check for randomization

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Exclusion Criteria

EXCLUSION CRITERIA
1. Congenital or acquired immunodeficiency
2. Systemic lymphoma manifestation (outside the CNS)
3. Isolated ocular lymphoma without manifestation in the brain parenchyma or spinal cord
4. Previous or concurrent malignancies with the exception of surgically cured carcinoma in-situ of the cervix, carcinoma of the skin or other kinds of cancer without evidence of disease for at least 5 years
5. Previous Non-Hodgkin lymphoma at any time
6. Only applicable for patient inclusion (registration) not applicable for recheck
for randomization. Inadequate bone marrow (platelet count decreased ≥CTC grade 1, anemia ≥CTC grade 1, neutrophil count decreased ≥CTC grade 1), renal (creatinine clearance <60 ml/min), cardiac (ejection fraction decreased ≥CTC grade 2), or hepatic function (blood bilirubin increased ≥CTC grade 2, alanine aminotransferase increased ≥CTC grade 2, aspartate aminotransferase increased ≥CTC grade 2 or gamma-GT increased ≥CTC grade 2)
7. HBsAg, anti-HBc and HCV positivity
8. HIV infection, previous organ transplantation or other clinical evident form of immunodeficiency
9. Concurrent treatment with other experimental drugs or participation in a clinical trial within the last thirty days before the start of this study
10. Symptomatic coronary artery disease, cardiac arrhythmias uncontrolled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease)
11. Severe non-compensated pulmonary disease (IVC <55%, DLCO <40%)
12. Third space fluid accumulation >500 ml
13. Hypersensitivity to study treatment or any component of the formulation
14. Taking any medications likely to cause interactions with the study medication
15. Known or persistent abuse of medication, drugs or alcohol
16. Patient without legal capacity and who is unable to understand the nature, significance and consequences of the study and without designated legal representative
17. Persons who are in a relationship of dependency/employment to the sponsor and/ or investigator
18. Any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
19. Concurrent (or planned) pregnancy or lactation
20. Fertile patients refusing to use safe contraceptive methods during the study.

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Addresses

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    • Klinik für Haematologie, Onkologie und Palliativmedizin, Stuttgart Cancer Center / Tumorzentrum Eva Mayr-StihlKlinikum Stuttgart
    • Mr.  Prof. Dr.med.  Gerald  Illerhaus 
    • Kriegsbergstr.60
    • 70174  Stuttgart
    • Germany
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    • Klinik für Haematologie, Onkologie und PalliativmedizinStuttgart Cancer Center / Tumorzentrum Eva Mayr-StihlKlinikum Stuttgart
    • Mr.  Prof.Dr.med.  Gerald  Illerhaus 
    • Kriegsbergstr.60
    • 70174  Stuttgart
    • Germany
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    • Universitaetsklinikum Freiburg Abteilung Innere Medizin I Haematologie, Onkologie und Stammzelltransplantation
    • Ms.  Dr.med.  Elisabeth  Schorb 
    • Hugstetter Straße 55
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung Dienstsitz Bonn
    • Heinemannstr. 2
    • 53175  Bonn
    • Germany
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    • Riemser Pharma GmbHvertreten durch die Geschäftsführung und/ oder Prokuristen
    • An der Wiek 7
    • 17493  Greifswald-Insel Riems
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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