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DNA Based Therapy with Diphtheria Toxin-A BC-819: A Phase 2b Marker Lesion Trial in Patients with Intermediate Risk Nonmuscle Invasive Bladder Cancer

2013; Lippincott Williams & Wilkins; Volume: 191; Issue: 6 Linguagem: Inglês

10.1016/j.juro.2013.12.011

1527-3792

Ofer N. Gofrit, Shalva Benjamin, Sarel Halachmi, Ilan Leibovitch, Zohar Dotan, Donald L. Lamm, Nahum Ehrlich, Vladimir Yutkin, Monique Ben‐Am, Abraham Hochberg,

Cancer Cells and Metastasis

No AccessJournal of UrologyAdult Urology1 Jun 2014DNA Based Therapy with Diphtheria Toxin-A BC-819: A Phase 2b Marker Lesion Trial in Patients with Intermediate Risk Nonmuscle Invasive Bladder Cancer Ofer N. Gofrit, Shalva Benjamin, Sarel Halachmi, Ilan Leibovitch, Zohar Dotan, Donald L. Lamm, Nahum Ehrlich, Vladimir Yutkin, Monique Ben-Am, and Abraham Hochberg Ofer N. GofritOfer N. Gofrit Hadassah Ein-Kerem Medical Center, Jerusalem, Israel , Shalva BenjaminShalva Benjamin Edith Wolfson Medical Center, Sackler Faculty of Medicine, Holon, Israel , Sarel HalachmiSarel Halachmi Bnai-Zion Medical Center, Haifa, Israel , Ilan LeibovitchIlan Leibovitch Meir Medical Center, Kfar Saba, Israel , Zohar DotanZohar Dotan Sheba Medical Center, Tel Hashomer, Israel , Donald L. LammDonald L. Lamm University of Arizona, Phoenix, Arizona , Nahum EhrlichNahum Ehrlich Hillel Yafe Medical Center, Hadera, Israel , Vladimir YutkinVladimir Yutkin Hadassah Ein-Kerem Medical Center, Jerusalem, Israel , Monique Ben-AmMonique Ben-Am BioCancell Ltd., Jerusalem, Israel , and Abraham HochbergAbraham Hochberg Hebrew University, Jerusalem, Israel View All Author Informationhttps://doi.org/10.1016/j.juro.2013.12.011AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: H19 is a paternally imprinted oncofetal gene expressed in various embryonic tissues and in 85% of bladder tumors but suppressed in the adult healthy bladder. BC-819 is a DNA plasmid that carries the gene for diphtheria toxin-A under regulation of the H19 promoter sequence. We assessed the efficacy and toxicity of intravesical BC-819 instillations to prevent tumor recurrence and ablate a marker lesion in a phase 2b trial. Materials and Methods: A total of 47 patients with recurrent, multiple nonmuscle invasive bladder tumors in whom prior intravesical therapy had failed underwent transurethral resection of all except 1 marker tumor. Patients expressing H19 received a 6-week induction course of intravesical BC-819. Patients who achieved a complete response (absent new tumors at 3 months) were given 3 maintenance courses of 3-weekly instillations every 3 months. Results: All patients were evaluable for adverse effects and 39 were evaluable for efficacy. Complete tumor ablation was achieved in 33% of patients and in 64% there were no new tumors at 3 months. Median time to recurrence was 11.3 months in all cases but significantly longer (22.1 months) when analyzed by response status at 3 months. Adverse events were mild. The study was limited by the small number of patients. Conclusions: BC-819 prevented new tumor growth in two-thirds of the patients and ablated a third of the marker lesions. Prolonged time to recurrence was observed in responding patients. These results along with the good safety profile make BC-819 a potential medication for bladder cancer. References 1 : Cancer statistics, 2012. CA Cancer J Clin2012; 62: 10. Google Scholar 2 : European Association of Urology (EAU). EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol2011; 59: 997. Google Scholar 3 : Possible physiological role of H19 RNA. Mol Carcinog2002; 35: 63. Google Scholar 4 : Imprinted H19 gene expression in embryogenesis and human cancer: the oncofetal connection. Am J Med Genet2000; 91: 46. Google Scholar 5 : The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma. Mol Pathol2000; 53: 320. Google Scholar 6 : Polymorphisms in the H19 gene and the risk of bladder cancer. Eur Urol2008; 54: 1118. Google Scholar 7 : Gene expression in the bladder carcinoma rat model. Mol Carcinog2004; 41: 69. 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A combined analysis of 2596 patients from seven EORTC trials. Eur Urol2006; 49: 466. Google Scholar 15 : Optimal two-stage designs for phase II clinical trials. Control Clin Trials1989; 10: 1. Google Scholar © 2014 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byNazmifar M, Williams C, Naser-Tavakolian A, Heard J, Rosser C, Theodorescu D and Ahdoot M (2022) Clinical and Preclinical Therapies for Bladder Cancer Following Bacillus Calmette-Guérin FailureJournal of Urology, VOL. 209, NO. 1, (32-48), Online publication date: 1-Jan-2023. Volume 191Issue 6June 2014Page: 1697-1702 Advertisement Copyright & Permissions© 2014 by American Urological Association Education and Research, Inc.Keywordscarcinomaurinary bladderplasmidsdiphtheria toxinurotheliumMetricsAuthor Information Ofer N. Gofrit Hadassah Ein-Kerem Medical Center, Jerusalem, Israel Financial interest and/or other relationship with BioCancell. More articles by this author Shalva Benjamin Edith Wolfson Medical Center, Sackler Faculty of Medicine, Holon, Israel More articles by this author Sarel Halachmi Bnai-Zion Medical Center, Haifa, Israel More articles by this author Ilan Leibovitch Meir Medical Center, Kfar Saba, Israel More articles by this author Zohar Dotan Sheba Medical Center, Tel Hashomer, Israel More articles by this author Donald L. Lamm University of Arizona, Phoenix, Arizona More articles by this author Nahum Ehrlich Hillel Yafe Medical Center, Hadera, Israel More articles by this author Vladimir Yutkin Hadassah Ein-Kerem Medical Center, Jerusalem, Israel More articles by this author Monique Ben-Am BioCancell Ltd., Jerusalem, Israel Financial interest and/or other relationship with BioCancell. More articles by this author Abraham Hochberg Hebrew University, Jerusalem, Israel Financial interest and/or other relationship with BioCancell. 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