First results of the methoglu Trial, a phase 1 Trial from the LOC network evaluating the reduction of the time interval between methotrexate perfusions combined with glucarpidase in relapsed primary CNS lymphomas

Abstract

Abstract Introduction High-dose methotrexate (hdMTX) is the key drug in primary central nervous system lymphoma (PCNSL). It is usually administrated every 2 or 3 weeks, at a dose ≥3 g/m2, according to most guidelines and chemotherapy protocols. Glucarpidase is a recombinant bacterial enzyme that cleaves circulating MTX into inactive metabolites within a few minutes. It is approved in the management of delay in MTX elimination. In order to improve the dose intensity of hdMTX, we aimed to investigate whether it would be possible to reduce the time interval between hdMTX perfusions by systematically associating hdMTX with glucarpidase. Methods We conducted an open-label multicenter phase 1 trial (NCT05135858). The main inclusion criteria were as follows: cerebral relapse of PCNSL (any line of treatment); pathological diagnosis of diffuse large B-cell lymphoma at initial diagnosis; hdMTX based chemotherapy in first-line treatment, with complete response lasting at least 6 months after the end of the first-line treatment; age>18 years; Karnofsky performance status (KPS) ≥50; glomerular filtration rate >60 ml/min. The regimen consisted of 6 cycles of hdMTX as a single agent at the fixed dose of 3.5 g/m2, systematically followed at H24 by glucarpidase administration (2000 units). We planned to follow a standard “3+3” dose level escalation design, with three reduced time intervals (8, 6 and 5 days) between hdMTX injections at fixed dose. The primary objective was to determine the minimum tolerated time interval between hdMTX perfusions. The primary endpoint was the occurrence of a dose schedule limiting toxicity (DLT) occurring before the 25th day after the first MTX infusion. Results Nine patients were included in the trial between September 2022 and May 2025, six at the 8-day time interval (8-DTI) and three at the 6-DTI. Their median age was 72 years (range: 42-84). Their median KPS was 60 (range: 50-90). There were five men and four women. Seven patients were on second-line treatment and two on third-line treatment. The median duration of disease before inclusion was 53 months (IQR 26-72). A total of 34 cycles of hdMTX associated with glucarpidase were administered. The patients included at the 8-DTI received a median of 6 cycles of MTX (range: 1-6), administered with a median interval of 8.01 days. Only one of them experienced a DLT, which consisted of a grade 3 renal toxicity after cycle 1, that completely resolved within a few weeks after protocol treatment discontinuation. Another patient of the 8-DTI prematurely discontinued the protocol because of a delay in MTX administration > 36 hours due to grade 2 thrombopenia after cycle 4, which did not constitute a DLT as it occurred after D25. Among the patients enrolled in the 6-DTI cohort, one was considered not evaluable as he prematurely discontinued the protocol after the first cycle because of a sepsis secondary to pyelonephritis. The two other patients of this group experienced a DLT, which consisted of a delay in MTX administration > 36 hours due respectively to grade 2 and grade 3 thrombopenia after cycle 2. According to the dose-escalation rule, no additional patients were included at the 6-DTI or at the 5-DTI, while the 8-DTI was validated. Overall, seven grade 3 toxicities (lymphopenia (N=3), thrombopenia (N=1), liver toxicities (N=2) and renal toxicity (N=1)) and two grade 4 toxicities (lymphopenia) related to the protocol treatment were reported. Regarding renal toxicity, one case of grade 1 renal toxicity occurred in addition to the previously described grade 3 toxicity. All the patients who did not experience DLT achieved an objective response at the end of the trial (Complete response: N=2; partial response: N=3). Two of them subsequently received ASCT, and one received CAR T-cell therapy (ASCT planned in one additional patient). These five patients were still alive and relapse-free at latest news (median follow-up of 29 months). Pharmacokinetics studies, anti-glucarpidase antibodies detection and neurocognitive evaluation analysis are currently ongoing. Conclusion Reducing the time interval between hdMTX perfusions to 8 days by using glucarpidase seems feasible and well-tolerated, especially with regard to renal function, in relapsed PCNSL. Considering these results, it was decided to add a 7-DTI to this trial. Further studies will then be necessary to determine whether this increase of dose intensity of hdMTX will result in improved efficacy in CNS lymphomas.