Title: CRUK/14/044 IELSG 42: International phase II trial assessing tolerability and efficacy of sequential MTX/Ara-C-based regimen and R-ICE, followed by high dose chemotherapy supported by PBSCT, in patients with systemic B-cell lymphoma with central nervous system involvement at diagnosis or relapse
Funder: Cancer Research UK

Abstract: Background Diffuse large B-cell lymphoma (DLBCL) involving the central nervous system (CNS) at diagnosis or relapse is associated with a dismal outcome. There is no standard treatment approach for such patients in the UK and there has never been a clinical trial addressing this. The majority of patients who present with aggressive lymphomas and CNS disease will experience an associated systemic dissemination, concomitant or shortly later. As a consequence, the treatment should be effective against both the systemic and the CNS localization of the disease. Thus a new HD-MTX-based chemotherapy for induction, followed by R-ICE (rituximab, ifosfamide, carboplatin, etoposide) combination, the MARIETTA regimen, has been developed, and will be used in the study. This regimen is based on two important anti-lymphoma chemotherapy principles: the positive effect of dose intensity/density and of combination of cytostatics active in different cell-cycle phases. MARIETTA regimen is also based on the positive experience of high doses of antimetabolites in the treatment of Primary CNS lymphoma, the encouraging preliminary results with high-dose ifosfamide, the well-documented efficacy of R-ICE regimen as induction treatment for patients with relapsed/refractory DLBCL, and positive effect of consolidation with BCNU-thiotepa-based conditioning supported by ASCT in patients with primary CNS lymphoma. MARIETTA drugs have been selected both for their well-documented anti-lymphoma activity as well as their high BBB penetration and CNS bioavailability. Importantly, sequential administration of R-ICE may result in reduced cross-resistance with antimetabolites, with a consequent improved efficacy. Aims This is an open, non comparative, multicentre phase II trial, to evaluate the efficacy and feasibility of a new sequential combination of HD-MTX-AraC-based chemoimmunotherapy, followed by R-ICE regimen, and by high-dose chemotherapy supported by PBSCT for patients with SCNSL (at initial diagnosis or relapse). Endpoints will include safety of the regimen, response rates (pre- and post-PBSCT) and survival (disease-free survival and overall survival). Methods Treatment will include 6 courses of chemoimmunotherapy. the first three courses with an HD-MTX-based combination followed by three courses of R-ICE combination followed by consolidation with a BCNU-thiotepa-containing conditioning regimen and subsequent PBSCT. Recruitment target is 67 assessable patients, which is expected to take approximately 3 years across Europe. How the results of this research will be used. This study will identify a novel approach to patients who present with secondary CNS lymphoma that has been assessed for feasibility of delivery in multiple centres in the UK and worldwide.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS