Ctni-05. intrathecal pemetrexed for leptomeningeal metastases from solid tumor: a multicenter, phase i/ii, open-label study (pmlm, nct 05289908)

Abstract OBJECTIVES This phase I/II study was to evaluate maximum tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation and antitumor activity for leptomeningeal metastases (LM) from solid tumors. METHODS Phase I study followed the classic 3 + 3 design, with dose escalated from 15 mg. Phase II followed Simon 2-stage design with recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. RESULTS Between Feb 2022 and Jan 2023, 34 patients were enrolled, including non-small cell lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs. Overall CRR was 41.2% (14/34), including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. Median survival was 7.6 (range 0.3–13.7) months in phase I, while has not yet been achieved in phase II. CONCLUSION MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.