A Phase I/II Dose-Escalation Study of Thiotepa-Based Immunochemotherapy in Relapsed/Refractory Primary Central Nervous System Lymphoma; The Tier Trial

BACKGROUND Outcomes for patients (pts) with primary CNS diffuse large B cell lymphoma (PCNSL) have improved over recent years, largely through optimisation of first-line methotrexate (MTX)-containing protocols and dose-intensive chemotherapy consolidation. However, 30-50% of pts experience refractory or relapsed (r/r) disease, which confers very poor outcomes and short survival. By contrast to systemic DLCBL, there is no accepted standard approach for r/r PCNSL. Thiotepa is an alkylating agent highly efficient at crossing the BBB and widely incorporated within high-dose therapy and autologous stem cell transplantation (HDT-ASCT) protocols for PCNSL, but has not undergone dose-finding studies nor been incorporated within salvage regimens for PCNSL. The TIER study investigates the safety and efficacy of adding thiotepa, in a dose-escalation design, to the Rituximab, Ifosphamide and Etoposide (R-IE) salvage regimen1. METHODS TIER is an open label, phase I/II UK NCRI TAP study for pts with r/r PCNSL, previously treated with a high-dose MTX-based regimen. In phase I, the RP2D of thiotepa within the TIER combination was established using a 3+3 design, with dose escalations of 30, 40 and 50mg/m2 (dose level 2 (n=4), 3 (n=5) and 4 (n=27) respectively), given on day 5 of R-IE cycle1. The Phase II primary endpoint was overall response rate (ORR) after cycle 2 of TIER (C2) by centrally reviewed contrast-enhanced MRI2, on an intention-to-treat (ITT) basis. Further treatment and consolidation after the primary endpoint MRI was at the discretion of investigators. Key secondary end-points were 2-year PFS, EFS and OS. RESULTS Thirty-six pts were recruited from Jun 2015-Apr 2019 at 13 centres (characteristics: Table 1). The median number of prior lines was 2 (range 1-4) with 44% of patients deemed refractory to their previous line of therapy. During phase I (n=10) no dose limiting toxicities (DLTs) were observed up to and including 50mg/m2 thiotepa, constituting the RP2D (n=27). 56 cycles of TIER were administered across both phases; 5 pts had >1 dose reductions. Median time between C1D1 and C2D1 was 24.7 days (range 22-38). Relative mean dose intensity of thiotepa, ifosphamide and etoposide was 71.8 (SD 44.9), 76.4 (SD 41.6), and 76.8 (SD 41.8) respectively. Further therapy after 2 cycles of TIER was delivered to 41.7% of pts (16.7% ASCT, 22.2% TIE, and 2.8% WBRT). The most common grade 3 / 4 adverse events were thrombocytopenia and neutropenia (47.2 and 55.6% occurring i