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, dexamethasone, etoposide, ifosfamide, carboplatin).
Trial purpose and rationale 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. Rationale for this study: Based on previously obtained good results from the treatment of recurrent or refractory PCNSL the DeVIC protocol was chosen for conventional consolidation treatment. This protocol, originally designed as a salvage protocol for aggressive NHL, crosses the blood-brain barrier and consists of multidrug resistant unrelated agents. Treatment plan and procedure Interventions Induction treatment 4 cycles (every 3 weeks), stem-cell harvest after 2nd cycle: * Rituximab 375 mg/m²/d i.v. (d 0,5) * Methotrexate 3,5 g/m² i.v. (d1) * Cytarabine 2 x 2 g/m²/d i.v. (d2-3) * Thiotepa 30 mg/m² i.v. (d4) Patients with PD after two cycles, SD/PD after four cycles of induction therapy or insufficient stem-cell harvest after three cycles are ineligible for randomization. Consolidation Arm A 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) Consolidation Arm B High-dose chemotherapy (HDT-ASCT): * Carmustine\* 400 mg/m² i.v. (d-6) * Thiotepa 2 x 5 mg/kg/d i.v. (d-5-(-4)) * Autologous Stem Cell Transplantation (d0) \* if carmustine is not available at the investigation site, busulfan can be administered instead: * Busulfan 3,2 mg/kg/d (d-8-(-7)) * Thiotepa 2 x 5 mg/kg/d i.v. (d-5-(-4)) * Autologous Stem Cell Transplantation (d0)
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
250
Arm A 4 cycles MATRix (every 3 weeks), stem-cell harvest after 2nd cycle: * Rituximab 375 mg/m²/d i.v. (d0,5) * Methotrexate 3.5 g/m² i.v. (d1) * Cytarabine 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)
4 cycles MATRix (every 3 weeks), stem-cell harvest after 2nd cycle: * Rituximab 375 mg/m²/d i.v. (d0,5) * Methotrexate 3.5 g/m² i.v. (d1) * Cytarabine 2 x 2 g/m²/d i.v. (d2-3) * Thiotepa 30 mg/m² i.v. (d4) Consolidation High-dose chemotherapy (HDT-ASCT): * Carmustine\* 400 mg/m² i.v. (d-6) * Thiotepa 2 x 5 mg/kg/d i.v. (d-5-(-4)) * Autologous Stem Cell Transplantation (d0) \* if carmustine is not available at the investigation site, busulfan can be administered instead: * Busulfan 3,2 mg/kg/d (d-8-(-7)) * Thiotepa 2 x 5 mg/kg/d i.v. (d-5-(-4)) * Autologous Stem Cell Transplantation (d0)
University Hospital Freiburg - Department for Hematology, Oncology and Stem cell Transplantion
Freiburg im Breisgau, Baden-Wurttemberg, Germany
RECRUITINGKlinikum Stuttgart, Clinic of Hematology, Oncology and Palliative Care, Stuttgart Cancer Center / Tumor Center Eva Mayr-Stihl
Stuttgart, Baden-Wurttemberg, Germany
RECRUITINGThe primary outcome measure PFS will be measured by the number of events (PD, relapse or death from any cause) within the treatment arms
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
Time frame: PFS is defined as the time from randomization until PD or relapse or death from any cause up to 24 months after end of treatment
The secondary outcome measure CR will be assessed on day 60 after randomization using the IPCG response criteria
Response will be measured by the IPCG response criteria.
Time frame: CR will be determined on day 60 after randomization
The secondary outcome measure Response duration will be measured by the time from CR, CRu or PR until relapse or PD using the IPCG response criteria
Response duration observation times for patients where the event of interest was not observed, will be censored at the time last seen alive. Timepoints of evaluation are defined as every assessment during follow up period in accordance with the protocol. year 1-2: every 3 month
Time frame: Time from CR, CRu or PR until relapse or PD up to 24 months after end of treatment
The secondary outcome OS is measured as time from randomization until death of any cause
Timepoints of evaluation are defined as every assessment during follow up period in accordance with the protocol. year 1-2: every 3 month
Time frame: OS is defined as time from randomization until death of any cause up to 24 months after end of treatment
Number of patients with (Serious) adverse events as assessed by CTCAE v4.0
After this time period, only SAEs judged by the investigator to be related to at least one of investigational products will be reported
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Time frame: All SAEs that occur starting from the first administration of the study medication until day 60 after randomization.
Number of patients with treatment related toxicity as assessed by CTCAE v4.0
If an abnormal parameter is not listed in the toxicity table, an AE must be documented
Time frame: All toxicities that occur starting from the first administration of the study medication until day 60 after randomization.
Number of patients with neurotoxicity assessed by MMSE, EORTC QLQ-BN20 and the neuro-psychological battery
Timepoints of evaluation are defined as every assessment during follow up period in accordance with the protocol
Time frame: All parameters of neurotoxicity that occur starting from the first administration of the study medication up to 24 months after end of treatment.