{"doi":"10.17615/6gs3-hm85","title":"Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma","abstract":"BACKGROUND: Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Molecular profiling studies reveal that the PI3K/AKT/mTOR pathway is altered in a significant percentage of UCs. OBJECTIVE: We conducted a phase I trial to evaluate the feasibility of combining the mTOR inhibitor everolimus with gemcitabine and split-dose cisplatin (GC) in advanced UC in the first-line setting. METHODS: Patients received gemcitabine 800 mg/m2 and cisplatin 35 mg/m2 on days 1 and 8 of 21-day cycles for a total of 6 cycles in combination with everolimus at increasing dose levels (DL1:5 mg QOD, DL2:5 mg daily, DL3:10 mg daily) following a standard 3+3 design. Responses were assessed every 2 cycles. Patients with at least stable disease (SD) continued everolimus until progression. Goals were to establish dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for the combination. RESULTS: 12 patients were enrolled, 3 at DL1, 3 at DL2, and an additional 6 at DL1 *(DL1 following de-escalation). 3/3 patients at DL2 had DLTs during cycle 1. 2/8 evaluable patients at DL1/DL1 * had DLTs during cycle 1. DLTs were primarily hematologic. Further toxicities, also primarily hematologic, were observed during later treatment cycles, leading to 8 chemotherapy dose reductions overall. Partial responses were observed in 4/10 evaluable patients, and SD in 5/10. Median overall survival was 10.8 months (95% CI 6.9, not reached). CONCLUSIONS: The maximum tolerated dose was reached at the lowest dose level, 5 mg QOD, for everolimus in combination with gemcitabine and split-dose cisplatin in advanced UC. The regimen was limited by hematologic toxicity.","journal":"UNC Libraries","year":2024,"id":501690,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":314353,"name":"Irina Ostrovnaya","orcid":"0000-0003-1783-0070","position":1,"is_corresponding":false},{"id":456370,"name":"Matthew I. Milowsky","orcid":"0000-0002-8965-8129","position":2,"is_corresponding":false},{"id":335058,"name":"Jonathan E. Rosenberg","orcid":"0000-0003-2637-4249","position":3,"is_corresponding":false},{"id":50783,"name":"Wassim Abida","orcid":"0000-0002-9006-7043","position":4,"is_corresponding":false},{"id":108820,"name":"Dean F. Bajorin","orcid":"0000-0003-4001-7088","position":5,"is_corresponding":false},{"id":1351285,"name":"Mariel Elena Boyd","orcid":null,"position":6,"is_corresponding":false},{"id":850399,"name":"Asia S. McCoy","orcid":null,"position":7,"is_corresponding":false},{"id":456369,"name":"Ashley Marie Regazzi","orcid":"0000-0002-6019-1852","position":8,"is_corresponding":false},{"id":263625,"name":"Andrea B. Apolo","orcid":"0000-0001-9409-1836","position":9,"is_corresponding":false},{"id":289279,"name":"Martin H. Voss","orcid":"0000-0003-0551-5807","position":10,"is_corresponding":false},{"id":1351284,"name":"Scott R. Gerst","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:10:15.999370Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}