High-dose Chemotherapy and ASCT or Consolidating Conventional Chemotherapy in Primary CNS Lymphoma

Study Overview
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Brief Summary
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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).

Detailed Description
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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)

Official Title
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High-dose Chemotherapy and Autologous Stem Cell Transplant or Consolidating Conventional Chemotherapy in Primary CNS Lymphoma - Randomized Phase III Trial

Conditions
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Diffuse Large B-cell-lymphoma

Intervention / Treatment
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* Drug: Arm A (Fortecortin®-ETOPOPHOS®-IFO-cell®-CARBO-cell®)
* Drug: Arm B (TEPADINA®-CARMUBRIS®-Busilvex®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Immunocompetent patients with newly-diagnosed primary central nervous system B-cell lymphoma Age 18-65 years irrespective of ECOG or 66-70 years (with ECOG Performance Status ≤2) 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 Disease exclusively located in the CNS At least one measurable lesion Previously untreated patients (previous or ongoing steroid treatment admitted) Sexually active patients of childbearing potential who agree to take adequate contraceptive measures during study participation 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 Sufficient stem cell harvest (≥ 5 x 106 CD34+ cells/kg of body weight) Complete remission, unconfirmed complete remission or partial remission Central pathology results confirming local results Exclusion Criteria: Congenital or acquired immunodeficiency Systemic lymphoma manifestation (outside the CNS) Isolated ocular lymphoma without manifestation in the brain parenchyma or spinal cord 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 Previous Non-Hodgkin lymphoma at any time 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) HBsAg, anti-HBc or HCV positivity HIV infection, previous organ transplantation or other clinical evident form of immunodeficiency Concurrent treatment with other experimental drugs or participation in a clinical trial within the last thirty days before the start of this study 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) Severe non-compensated pulmonary disease (IVC <55%, DLCO <40%) Third space fluid accumulation >500 ml Hypersensitivity to study treatment or any component of the formulation Taking any medications likely to cause interactions with the study medication Known or persistent abuse of medication, drugs or alcohol Patient without legal capacity and who is unable to understand the nature, significance and consequences of the study and without designated legal representative Persons who are in a relationship of dependency/employment to the sponsor and/ or investigator Any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Concurrent (or planned) pregnancy or lactation Fertile patients refusing to use safe contraceptive methods during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Induction Treatment 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 Treatment 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) | Drug: Arm A (Fortecortin®-ETOPOPHOS®-IFO-cell®-CARBO-cell®)<br>* 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)<br>* Other names: Fortecortin®-ETOPOPHOS®-IFO-cell®-CARBO-cell®;|
| Active Comparator: Arm B<br>Induction Treatment 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 Treatment High-dose chemotherapy 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 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)) Autologous Stem Cell Transplantation (d0) | Drug: Arm B (TEPADINA®-CARMUBRIS®-Busilvex®)<br>* 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)<br>* Other names: TEPADINA®-CARMUBRIS®-Busilvex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The 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 | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 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 | 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 | 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 | 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 | All parameters of neurotoxicity that occur starting from the first administration of the study medication up to 24 months after end of treatment. |