In the presently planned multicentre Phase III trial the two therapies will be compared: Patients will be randomized after intensified induction treatment with 4 cycles rituximab, methotrexate, cytarabine and thiotepa (MATRix) between first-line high-dose chemotherapy against conventional consolidating therapy with 2 cycles of conventional chemotherapy with R-DeVIC (Rituximab, Dexamthason, Etoposide, Ifosfamide, Carboplatin).

• Register: EUCTR
• Last refreshed on: 23 October 2023
• Main ID: EUCTR2012-000620-17-DE
• Date of registration: 20/02/2014
• Prospective Registration: Yes
• Primary sponsor: Landeshauptstadt Stuttgart, represented by the Executive Medical Director Klinikum Stuttgart
• Public title: In the presently planned multicentre Phase III trial the two therapies will be compared: Patients will be randomized after intensified induction treatment with 4 cycles rituximab, methotrexate, cytarabine and thiotepa (MATRix) between first-line high-dose chemotherapy against conventional consolidating therapy with 2 cycles of conventional chemotherapy with R-DeVIC (Rituximab, Dexamthason, Etoposide, Ifosfamide, Carboplatin).
• Scientific title: High-dose chemotherapy and autologous stem cell transplant or consolidating conventional chemotherapy in primary CNS lymphoma - randomized phase III trial - MATRix / IELSG43
• Date of first enrolment: 28/04/2014
• Target sample size: 330
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-000620-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Comparison consolidation therapy:Arm A Consolidation 2 cycles of R-DeVIC - Arm B HDT-ASCT Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Czechia, Denmark, Germany, Italy, Norway, Switzerland

Contacts

• Name: Elvira Burger, Projektmanagement
• Affiliation: Studienzentrum Universitaetsklinikum Freiburg

• Name: Elvira Burger, Projektmanagement
• Affiliation: Studienzentrum Universitaetsklinikum Freiburg

Key inclusion & exclusion 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. Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist. Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy
4. Disease exclusively located in the CNS
5. At least one measurable lesion
6. Previously untreated patients (previous or ongoing steroid treatment admitted)
7. Sexually active patients of childbearing potential who agree to take adequate contraceptive measures during study participation
8. 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 (= 5 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


Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 265
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 65

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 re-check 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 (for details see clinical trial protocol section 4.3)



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Primary CNS lymphoma (PCNSL) accounts for 1 to 2% of all Non-Hodgkin's lymphomas (NHL) and for 2 to 7% of all primary CNS tumors. It's incidence has increased over the past 30 years, particularly in immunocompetent individuals. Over 90% of PCNSL are lymphomas of B-cell origin, accounting to the subtype diffuse large B-cell lymphoma. (DLBCL). Prognosis without treatment resembles that of systemic high-grade NHL, and the median survival of untreated patients with PCNSL is approximately 3 months.

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: Rituximab
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Product Name: Methotrexate
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: METHOTREXATE DISODIUM
CAS Number: 7413-34-5
Other descriptive name: MTX, IUPAC: (2S)-2-[[4-[(2, 4-diaminopteridin-6-yl)methylmethylamino] benzoyl]amino]pentanedioate disodium
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Cytarabine
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: CYTARABINE
CAS Number: 147-94-4
Other descriptive name: Cytosine Arabinoside, Arabinofuranosylcytosin, Ara-C, IUPAC: 4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] pyrimidin-2-one
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Product Name: Thiotepa
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: THIOTEPA
CAS Number: 52-24-4
Other descriptive name: IUPAC: 1,1',1''-phosphorothioyltriaziridine
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Product Name: Carmustine
Pharmaceutical Form: Powder and solvent for solution for infusion
INN or Proposed INN: CARMUSTINE
CAS Number: 154-93-8
Other descriptive name: BCNU, Bischlorethylnitrosourea, IUPAC: 1,3-Bis(2-chloroethyl)-1-nitrosourea
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 3-

Product Name: Dexamethasone
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DEXAMETHASONE-21-DIHYDR

Primary Outcome(s)

Main Objective: To demonstrate the efficacy measured as progression-free survival (PFS) of intensive chemotherapy followed by autologous stem-cell transplantation compared to conventional chemotherapy

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

Timepoint(s) of evaluation of this end point: Progression-free survival PFS:
Response Assessment III at the end of study treatment (EOT) visit and every imaging diagnostic assessments during follow-up period (for details see protocol intervention scheme, page 19):
during year 1-2: every 3 month
recommeded for year 3-5: every 6 month
recommeded for > year 5 annually
or imaging in case of clinical suspicion of disease progression or relapse

Secondary Objective: To compare high-dose chemotherapy followed by autologous stem cell transplantation with optimized conventional chemotherapy regarding OS, treatment response and treatment related morbidities (neurotoxicity and adverse advents) in patients with primary CNS lymphoma.

Secondary Outcome(s)

Secondary end point(s): Secondary endpoints:
Efficacy:
• Complete response (CR)
• Response duration
• Overall survival (OS)
• Quality of life (QOL): EORTC QLQ-C30
Safety:
• (Serious) adverse events
• Toxicity
• Neurotoxicity (MMSE, EORTC QLQ-BN20, neuropsychological test battery)

Timepoint(s) of evaluation of this end point: CR will be determined on day 60 after randomization.

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.

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
recommended for year 3-5: every 6 month
reccommended for > year 5 annually

Secondary ID(s)

NCT02531841

DRKS00005503

00005503

Source(s) of Monetary Support

Federal Ministry for Education and Research (BMBF)

Ethics review

Status: Approved
Approval date: 15/04/2014
Contact: