1. Neoadjuvant sorafenib, gemcitabine, and cisplatin administration preceding cystectomy in patients with muscle-invasive urothelial bladder carcinoma: An open-label, single-arm, single-center, phase 2 study
- Author
-
Maurizio Colecchia, Silvia Stagni, Nicola Nicolai, Luigi Mariani, Adele Busico, Nadia Zaffaroni, Daniele Raggi, Salvatore Lo Vullo, Federica Perrone, Patrizia Giannatempo, Luigi Piva, Marzia Pennati, Davide Biasoni, Elena Togliardi, Mario Catanzaro, Andrea Necchi, Roberto Salvioni, Tullio Torelli, Giuseppina Calareso, Necchi, A, Lo Vullo, S, Raggi, D, Perrone, F, Giannatempo, P, Calareso, G, Togliardi, E, Nicolai, N, Piva, L, Biasoni, D, Catanzaro, M, Torelli, T, Stagni, S, Colecchia, M, Busico, A, Pennati, M, Zaffaroni, N, Mariani, L, and Salvioni, R
- Subjects
Sorafenib ,Oncology ,Male ,Niacinamide ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,030232 urology & nephrology ,Phases of clinical research ,Cystectomy ,Deoxycytidine ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Carcinoma ,Humans ,Neoadjuvant therapy ,Aged ,Bladder cancer ,business.industry ,Phenylurea Compounds ,Middle Aged ,medicine.disease ,Gemcitabine ,Treatment Outcome ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Female ,Cisplatin ,business ,medicine.drug - Abstract
Background Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676). Patients and methods After transurethral resection of the bladder, T2–T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400 mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: ≤0.20 and H1: ≥0.40, with a type I and type II error of 5% and 10%, respectively. Results From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9–58.9); pT ≤ 1 in 25 (54.3%, 95% CI: 39.0–69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6–NR), nor was median overall survival (interquartile range: 30.3–NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT ≤ 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin-remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT ≤ 1 response ( P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution. Conclusions SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy.
- Published
- 2018