Primary Central Nervous System Lymphoma
Conditions
Keywords
Primary central nervous system lymphoma, HD-chemotherapy followed by autologous stem cell transplantation, Age-adjusted HCT-ASCT, First-line treatment in elderly PCNSL patients, HD-MTX induction
Brief summary
Most patients being diagnosed with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) are 60 years or older. Elderly patients with PCNSL have a poor prognosis and there is a great medical need to improve outcome for this vulnerable population. In Germany and many international centres, there are currently two widely used strategies to treat elderly PCNSL patients who are eligible for high-dose methotrexate (HD-MTX) treatment, which have not yet been compared head-to-head. The R-MP regimen has been established by the Cooperative PCNSL Study Group as a conventional immunochemotherapy standard treatment for elderly patients with newly diagnosed disease and consists of Rituximab, HD-MTX and Procarbazine followed by maintenance therapy with Procarbazine. In contrast, another recently established protocol also includes HD-MTX-based induction therapy, but followed by consolidating high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT). This is an overall more intensive, but substantially shorter treatment approach, feasible for elderly patients being considered eligible for a more intensive treatment. The PRIMA-CNS trial aims to compare these two treatment approaches with respect to survival, response rates and toxicity.
Detailed description
Primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is a rare lymphoma affecting only the central nervous system compartment. PCNSL patients are typically 60 years or older and have poor prognoses. However, there are alternative treatment approaches to consider with the potential to improve medical outcomes for this patient population. The current standard of care in Germany and many international centres for patients 65 and older is treatment with R-MP, comprising rituximab, high-dose methotrexate (HD-MTX) and procarbazine followed by maintenance therapy with procarbazine. An alternative approach comprised of a shorter induction treatment with rituximab, HD-MTX and cytarabine (MARTA) followed by age-adjusted high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) was recently shown to be feasible and effective in elderly PCNSL patients considered eligible for high-dose chemotherapy requiring autologous stem cell transplantation. Nevertheless, data evaluating this short duration treatment approach remains scarce, and randomized trials have not yet been published. The objective of the PRIMA-CNS trial is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with R-MP followed by maintenance with procarbazine in elderly patients with newly diagnosed PCNSL; not only regarding survival and remission after treatment but also regarding standards like quality of life (QOL) and treatment related morbidities. Results of this randomized trial will either change the standard of care to an intense and shorter treatment approach or re-define R-MP as a proven treatment standard. In addition, a geriatric assessement is implemented in this trial with the goal to better define transplant eligibility. If this trial shows the superiority of HCT-ASCT, the investigators will establish an improved treatment standard with increased chances for long-term remission and cure and reduced frequency and length of chemotherapy treatment. Considering the poor prognosis of this patient population, this randomized phase III trial is of great clinical importance to provide patients, the patients' families and care takers with optimal treatment.
Interventions
DRUGR-MP and Procarbazine maintenance
Firstline systemic treatment with conventinal immunochemotherapy (3 cycles of Rituximab-MTX-Procarbazine) followed by Procarbazine maintenance
DRUGR-MTX/AraC (MARTA) induction followed by consolidating HCT-ASCT
Firstline systemic treatment with age-adjusted MTX based induction (2 cycles of Rituximab-Methotrexate-Cytarabin) followed by consolidating aged-adapted high-dose chemotherapy and autologous stem cell transplantation
Sponsors
German Federal Ministry of Education and Research
University Hospital Tuebingen
Heinrich-Heine University, Duesseldorf
Klinikum Stuttgart
University of Kaiserslautern
University Hospital Munich
University Hospital Regensburg
University Hospital Freiburg
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a randomized, controlled, open-label, multicenter phase III trial with 2 parallel arms investigating a more intensive, shorter treatment with 2 cycles of MARTA (rituximab, HD-MTX, AraC) followed by HCT with rituximab, busulfan and thiotepa followed by ASCT compared to standard therapy comprising 3 cycles of R-MP followed by procarbazine maintenance for 6 months.
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Immunocompetent patients with newly-diagnosed primary DLBCL of the central nervous system. 2. Age \> 70 years or age 65-70 years if not eligible for more intensive treatment (e.g. OptiMATe trial). 3. Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist. 4. Diagnostic sample obtained by stereotactic or surgical biopsy, cerebrospinal fluid (CSF) cytology examination or vitrectomy. 5. Disease exclusively located in the CNS. 6. At least 1 measurable lesion. 7. Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) ≤ 2. ECOG PS \> 2 accepted if due to PCNSL symptoms. 8. Patients possibly eligible for HCT-ASCT as judged by the treating physician. 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. Patients eligible for HCT-ASCT defined by the EBL score (at most one of the 3 following conditions may apply: ECOG PS \> 1, Barthel Index of activities of daily living (ADL) \< 20 and Lachs geriatric screening \> 3), improvement of PS after pre-phase treatment or clinical judgement by the treating physician after discussion with the study expert team. 2. No evidence of disease progression after pre-phase treatment.
Exclusion criteria
1. Congenital or acquired immunodeficiency including HIV infection and previous organ transplantation. 2. Systemic lymphoma manifestation (outside the CNS). 3. Primary vitreoretinal lymphoma or primary leptomeningeal lymphoma without manifestation in the brain parenchyma or spinal cord. 4. Previous or concurrent malignancies with the exception of surgically cured carcinoma in situ or other kinds of cancer without evidence of disease for at least 5 years. 5. Previous systemic Non-Hodgkin lymphoma at any time. 6. Inadequate renal function (creatinine clearance \<60 ml/min). 7. Inadequate bone marrow, cardiac, pulmonary or hepatic function according to investigator´s decision. 8. Active hepatitis B or C disease. 9. Concurrent treatment with other experimental drugs or participation in an interventional clinical trial with administration of study medication within the last thirty days before the start of this study. 10. Third space fluid accumulation \>500 ml. 11. Hypersensitivity to study treatment or any component of the formulation. 12. Taking any medications likely to cause interactions with the study medication. 13. Known or persistent abuse of medication, drugs or alcohol. 14. Active COVID-19-infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic. 15. Patients without legal capacity and who are unable to understand the nature, significance and consequences of the study and without designated legal representative. 16. Previous participation in this trial. 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. Fertile patients refusing to use safe contraceptive methods during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) between the 2 arms | up to 6 years | PFS is defined as the time from randomization to disease progression or death of any cause, with censoring at the last date the patient was seen alive and free of disease progression |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission status after 2 cycles of rituximab-methotrexate-procarbazine (R-MP) (arm A)/2 cycles of R-MTX/cytarabine (AraC) | at RA I: after 8 weeks (Arm A), after 6 weeks (Arm B) | Remission status after 2 cycles of RMP (arm A) / 2 cycles of R-MTX/AraC will be determined at response assessment (RA) I in both arms and will be divided in complete remission (CR), unconfirmed complete remission (CRu), partial remission (PR), stable disease (SD), progressive disease(PD) according to international PCNSL collaborative group (IPCG) criteria |
| Remission status after 3 cycles of R-MP (arm A)/consolidating HCT-ASCT (arm B) | at RA II: after 12 weeks | determined at response assessment (RA) II and will be divided in CR, CRu, PR, SD, PD according to IPCG criteria |
| Remission status after completion of maintenance treatment (arm A)/6 months follow-up (arm B) | 6 months after RA II | will be determined 6 months after RA II and will be divided in CR, CRu, PR, SD, PD according to IPCG criteria |
| Quality of life (EORTC QLQ-C30) | from date of informed consent form (ICF) signature up to 6 years | EORTC quality of life questionnaire (QLQ)-C30 performed at screening, at RA II /premature EOT and thereafter every 12 months during follow-up |
| Quality of Life (EORTC-QLQ BN 20) | from date of informed consent form (ICF) signature up to 6 years | EORTC-QLQ brain neoplasm (BN) 20, performed at screening, at RA II /premature EOT and thereafter every 12 months during follow-up |
| Overall survival (OS) between the 2 arms | up to 6 years | OS is defined as time from randomization until death from any cause, with censoring at the last date the patient was seen alive |
| Event free survival (EFS) between the 2 arms | up to 6 years | EFS, defined as time from randomization to premature end of treatment (EOT) due to any reason, lymphoma progression or death, whichever occurs first, with censoring at the last date the patient was seen event-free |
Other
| Measure | Time frame | Description |
|---|---|---|
| Unplanned hospital admissions | from date of informed consent form (ICF) signature until 30 days after ASCT or 30 days after last administration of investigational medicinal products (IMP) | Defined as in-patient hospitalization due to SAE from date of informed consent form (ICF) signature until 30 days after ASCT or day 30 after last administration of IMP, whatever occurs first. Each hospitalization will be counted as a single event. |
| Length of hospital stays | from date of informed consent form (ICF) signature until 30 days after ASCT or day 30 after last administration of IMP | Measured as number of nights in hospital due to SAE as defined above, i.e. hospital stays from date of ICF signature until 30 days after ASCT or day 30 after last administration of IMP, whatever occurs first. |
| Safety: Toxicity | from date of informed consent form (ICF) signature until 30 days after end of treatment | Incidence of (Serious) adverse events ((S)AE) as assessed by CTCAE v5.0 |
| Safety: Neurotoxicity | from date of informed consent form (ICF) signature up to 6 years | Results in the following neuropsychological tests: Montreal Cognitive Assessment (MoCA), Trail Making Test A and B, the Rey-Osterrieth-Complex-Figure-Test and a verbal fluency test, performed at screening, RA II / premature EOT and every 12 months during follow-up. |
Countries
Germany
Contacts
Primary ContactElisabeth Schorb, MD
Backup ContactGerald Illerhaus, MD
Outcome results
None listed