{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T13:19:38Z","timestamp":1792847978051,"version":"4.5.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T00:00:00Z","timestamp":1670025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Src is overexpressed in various cancers, including 27% of non-small cell lung cancer NSCLC, and is correlated with poor clinical outcomes. We hypothesize that Src kinase inhibitors, including Bosutinib, may exhibit clinical synergy in combination with the antifolate drug pemetrexed. In this Phase I, dose-escalation, safety, and maximum tolerated dose (MTD)-determining study, 14 patients with advanced metastatic solid tumors that had progressed on \u201cstandard of care\u201d chemotherapy were enrolled in a 3 + 3 dose escalation study. Oral Bosutinib was administered once daily beginning on day 1, where the first cohort started at an oral dose of 200 mg daily with pemetrexed 500 mg\/m2 IV on a three-week schedule. The study\u2019s primary objective was to determine the dose-limiting toxicity (DLT), the MTD of Bosutinib in combination with pemetrexed, and the type and frequency of adverse events associated with this treatment. Twelve patients were evaluable for response, including ten patients with adenocarcinoma of the lung, one patient with metastatic adenocarcinoma of the appendix, and one patient with urothelial carcinoma. The median number of Bosutinib and pemetrexed cycles received was 4 (range, 1\u20134). The MTD of oral Bosutinib in this combination was 300 mg daily. Two patients (17%) had a partial response (PR), and seven patients (58%) showed stable disease (SD) as the best response after the fourth cycle (end of treatment). One patient had disease progression after the second cycle, while three patients had disease progression after the fourth cycle. The two responders and the two patients with the longest stable disease duration or stabilization of disease following progression on multiple systemic therapies demonstrated Src overexpression on immunohistochemical staining of their tumor. The median progression-free survival (PFS) was 6.89 months (95% CI (3.48, 30.85)), and the median overall survival (OS) was 11.7 months (95% CI (3.87, 30.85)). Despite the limitations of this Phase I study, there appears to be potential efficacy of this combination in previously treated patients.<\/jats:p>","DOI":"10.3390\/curroncol29120744","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T11:02:10Z","timestamp":1670238130000},"page":"9461-9473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Phase I Study of the Non-Receptor Kinase Inhibitor Bosutinib in Combination with Pemetrexed in Patients with Selected Metastatic Solid Tumors"],"prefix":"10.3390","volume":"29","author":[{"given":"Nagla Abdel","family":"Karim","sequence":"first","affiliation":[{"name":"Department of Medicine, Inova Schar Cancer Institute, University of Virginia, Fairfax, VA 22031, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9435-9625","authenticated-orcid":false,"given":"Asad","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongkun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Statistics, Georgetown University, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahran","family":"Shoukier","sequence":"additional","affiliation":[{"name":"Department of Hematology-Oncology, Georgia Cancer Center, Augusta, GA 30906, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Pulliam","sequence":"additional","affiliation":[{"name":"Department of Surgery, The University of Tennessee at Chattanooga, Chattanooga, TN 37403, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Khaled","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology-Oncology, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9335-0082","authenticated-orcid":false,"given":"Nikhil","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Augusta University Medical Center, Augusta, GA 30906, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology-Oncology, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1084\/jem.13.4.397","article-title":"A sarcoma of the fowl transmissible by an agent separable from the tumor cells","volume":"13","author":"Rous","year":"1911","journal-title":"J. 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