Intrathecal pemetrexed for newly diagnosed leptomeningeal metastases: A multicenter, open-label, phase I/II study

Background This phase I/II study evaluated the maximum-tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation, and its safety, feasibility and therapeutic activity for newly diagnosed leptomeningeal metastasis (LM) from solid tumors. Methods The phase I study followed the classic 3 + 3 design, with IP dose escalating from 15 mg. The recommended dose was applied in the phase II study. The MTD, adverse events (AEs), overall survival (OS), clinical response rate (CRR) and disease control rate (DCR) were evaluated. Results A total of 34 patients were enrolled. In the phase I study, 2 patients in the 20 mg group experienced dose-limiting toxicity. The MTD was established as 15 mg. Among 28 patients in the MTD group, 24 completed induction therapy, 19 completed consolidation therapy and 11 proceeded to maintenance therapy. The overall AEs rate was 74% (25/34), and severe AEs rate (> grade 3) was 15% (5/34). In the MTD group, the CRR, DCR and median OS were 46% (13/28), 75% (21/28) and 8.1 months. Conclusion IP at 15 mg with prior folic acid and vitamin B12 supplementation demonstrated safety and feasibility, offering a new treatment option with therapeutic activity for newly diagnosed LM patients with solid tumors. Trial registration: ClinicalTrials.gov Identifier: NCT05289908