{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:26:50Z","timestamp":1790803610129,"version":"4.1.0"},"reference-count":29,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"unspecified","delay-in-days":22,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["YG2025QNB42"],"award-info":[{"award-number":["YG2025QNB42"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272665"],"award-info":[{"award-number":["82272665"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272913"],"award-info":[{"award-number":["82272913"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573301"],"award-info":[{"award-number":["82573301"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573877"],"award-info":[{"award-number":["82573877"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Clinical Research Special Fund Project of Shanghai Chest Hospital","award":["2024IIT-Q010"],"award-info":[{"award-number":["2024IIT-Q010"]}]},{"DOI":"10.13039\/100017723","name":"Innovent Biologics","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/100017723","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,3,2]]},"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The prolonged survival of lung cancer patients is accompanied by an increasing incidence of leptomeningeal metastases (LM). Patients with LM have a poor prognosis, significantly impacting their quality of life and overall survival. Recent studies have shown that while intrathecal pemetrexed (IP) can improve symptoms and confer a survival benefit in non-small cell lung cancer (NSCLC) patients with LM, drug resistance remains a significant challenge. As for systemic therapy, intravenous bevacizumab combined with chemotherapy has demonstrated clinical benefits in NSCLC patients. However, clinical data on intrathecal bevacizumab remain scarce. Therefore, this study aims to preliminarily explore the efficacy and safety of intrathecal pemetrexed and bevacizumab in the treatment of NSCLC patients with LM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This is a single-centre, single-arm, prospective, investigator-initiated phase Ia clinical trial sponsored by Shanghai Chest Hospital, involving patients with advanced NSCLC and LM. Participants will be enrolled and allocated into two predefined cohorts. Cohort A: six participants will receive IP monotherapy for safety exploration. Cohort B: participants will receive intrathecal pemetrexed and bevacizumab. Pemetrexed will be administered at a fixed dose, while the dosage exploration for bevacizumab will employ a combination of a 3+3 design and an accelerated titration design (ATD). The primary endpoint is the safety and the secondary endpoint is the overall survival (OS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>This study protocol (Version 1.1, dated 8 October 2024) was approved by the Ethics Commission of Shanghai Chest Hospital (IS24103) on 23 October 2024. Trial results will be published in a peer-reviewed journal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT06663306\">NCT06663306<\/jats:ext-link>\n                      , ClinicalTrials.gov.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2026-116187","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T16:20:38Z","timestamp":1774282838000},"page":"e116187","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Safety and efficacy of intrathecal pemetrexed and bevacizumab in non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM): protocol for a single-arm, prospective, phase Ia trial"],"prefix":"10.1136","volume":"16","clinical-trial-number":[{"clinical-trial-number":"nct06663306","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06663306","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-7854","authenticated-orcid":false,"given":"Yanbin","family":"Kuang","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajun","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department 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