Clinical Trials and Emerging Therapeutic Strategies in Bladder Cancer

  • Richard M. BamburyEmail author
  • Robert B. Sims
  • Jonathan E. Rosenberg


The development of new and improved therapeutics is a key goal of the oncology community and such efforts are ongoing in the field of bladder cancer. In this chapter, we discuss the objectives, design and suitable endpoints for phase I, II and III clinical trials in the setting of bladder cancer. We discuss the historical difficulties that have been encountered when attempting to accrue patients to bladder cancer trials due to an elderly population with smoking-related co-morbidities.

Signaling pathway blockade through use of compounds which inhibit oncogenic proteins has proven efficacy in other cancers and efforts to develop this approach in bladder cancer are discussed. Examples of potentially targetable mutations in this advanced bladder cancer include the HER2 encoding ERBB2 gene which is amplified in approximately 5 % of cases, PIK3CA which is mutated in approximately 20 %, CDKN2A which is inactivated in 25 %, and FGFR3 which is activated in 10–15 %. Emerging immunotherapy and anti-angiogenic strategies under investigation in bladder cancer are also discussed.


Bladder cancer Urothelial cancer Clinical trials Oncogene Targeted therapy Immunotherapy Anti-angiogenic 


  1. 1.
    Leventhal B, Wittes R. Research methods in clinical oncology. New York, NY: Raven; 1988.Google Scholar
  2. 2.
    DeVita V, Lawrence T, Rosenberg S. DeVita, Hellman, and Rosenberg’s Cancer: principles & practice of oncology. 9th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.Google Scholar
  3. 3.
    Simon RM et al. Clinical trial designs for the early clinical development of therapeutic cancer vaccines. J Clin Oncol. 2001;19(6):1848–54.PubMedGoogle Scholar
  4. 4.
    Eisenhauer EA et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.PubMedCrossRefGoogle Scholar
  5. 5.
    Seymour L et al. The design of phase II clinical trials testing cancer therapeutics: consensus recommendations from the clinical trial design task force of the national cancer institute investigational drug steering committee. Clin Cancer Res. 2010;16(6):1764–9.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Simon R, Maitournam A. Evaluating the efficiency of targeted designs for randomized clinical trials. Clin Cancer Res. 2004;10(20):6759–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Lindeman NI et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823–59.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.PubMedCrossRefGoogle Scholar
  10. 10.
    Grossman HB et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–66.PubMedCrossRefGoogle Scholar
  11. 11.
    Paz-Ares LG, et al. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. ASCO meeting abstracts, 2010;28 (18_suppl):LBA4518.Google Scholar
  12. 12.
    Dalbagni G et al. Phase II trial of intravesical gemcitabine in bacille Calmette-Guerin-refractory transitional cell carcinoma of the bladder. J Clin Oncol. 2006;24(18):2729–34.PubMedCrossRefGoogle Scholar
  13. 13.
    Brausi MA et al. Can gemcitabine instillation ablate solitary low-risk non-muscle-invasive bladder cancer? Results of a phase II marker lesion study. Urol Int. 2011;87(4):470–4.PubMedCrossRefGoogle Scholar
  14. 14.
    James AC, Gore JL. The costs of non-muscle invasive bladder cancer. Urol Clin North Am. 2013;40(2):261–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Raj GV et al. Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer. J Urol. 2007;177(4):1283–6. discussion 1286.PubMedCrossRefGoogle Scholar
  16. 16.
    Hussain MH et al. Bladder cancer: narrowing the gap between evidence and practice. J Clin Oncol. 2009;27(34):5680–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Network NCC. Bladder cancer, Version 1.2013. NCCN guidelines for bladder cancer management. Accessed July 3, 2013.
  18. 18.
    Torti D et al. A preclinical algorithm of soluble surrogate biomarkers that correlate with therapeutic inhibition of the MET oncogene in gastric tumors. Int J Cancer. 2012;130(6):1357–66.PubMedCrossRefGoogle Scholar
  19. 19.
    Weinstein IB. Cancer. Addiction to oncogenes – the Achilles heal of cancer. Science. 2002;297(5578):63–4.PubMedCrossRefGoogle Scholar
  20. 20.
    O’Brien SG et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004.PubMedCrossRefGoogle Scholar
  21. 21.
    Chapman PB et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Rosell R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46.PubMedCrossRefGoogle Scholar
  23. 23.
    Carvajal RD. Another option in our kit of effective therapies for advanced melanoma. J Clin Oncol. 2013;31(26):3173–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Iyer G et al. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol. 2013;31(25):3133–40.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Balar AV, et al. Alterations in the PI3K/Akt signaling pathway and association with outcome in invasive high-grade urothelial cancer in American Society of Clinical Oncology 2012 Genitourinary Cancers Symposium, San Francisco, CL; 2012.Google Scholar
  26. 26.
    Iyer G et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Tomlinson DC et al. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007;213(1):91–8.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet. 2013;22(4):795–803.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Milowsky MI, et al. Final results of a multicenter, open-label phase II trial of dovitinib (TKI258) in patients with advanced urothelial carcinoma with either mutated or nonmutated FGFR3. In: ASCO 2013 Genitourinary Cancers Symposium, Orlando, FL; 2013.Google Scholar
  30. 30.
    Finn RS, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (BC). In: San Antonio breast Cancer Symposium 2012. San Antonio, TX; 2012.Google Scholar
  31. 31.
    Dean JL et al. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle. 2012;11(14):2756–61.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    McClendon AK et al. CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle. 2012;11(14):2747–55.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Moja L et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4, CD006243.PubMedGoogle Scholar
  34. 34.
    Bang YJ et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.PubMedCrossRefGoogle Scholar
  35. 35.
    Chaux A et al. High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded archival tissues. Hum Pathol. 2012;43(10):1590–5.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Comperat E et al. Gene expression study of Aurora-A reveals implication during bladder carcinogenesis and increasing values in invasive urothelial cancer. Urology. 2008;72(4):873–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Lei Y et al. Prognostic significance of Aurora-A expression in human bladder cancer. Acta Histochem. 2011;113(5):514–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Matulonis UA et al. Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Gynecol Oncol. 2012;127(1):63–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Richardson PG et al. Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers. Br J Haematol. 2011;152(4):367–79.PubMedCrossRefGoogle Scholar
  40. 40.
    Garg M et al. Heat-shock protein 70–2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion. Eur J Cancer. 2010;46(1):207–15.PubMedCrossRefGoogle Scholar
  41. 41.
    Kamada M et al. Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells. Mol Cancer Ther. 2007;6(1):299–308.PubMedCrossRefGoogle Scholar
  42. 42.
    Hadaschik BA et al. Intravesically administered antisense oligonucleotides targeting heat-shock protein-27 inhibit the growth of non-muscle-invasive bladder cancer. BJU Int. 2008;102(5):610–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Shelley MD et al. Intravesical bacillus calmette-guerin in Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2000;4, CD001986.PubMedGoogle Scholar
  44. 44.
    Kawai K et al. Bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer: current understanding and perspectives on engineered BCG vaccine. Cancer Sci. 2013;104(1):22–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Press MF, et al. HER2 expression in patients with surgically resected urothelial cancer at high risk of recurrence screened for the phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy targeting HER2. In: ASCO Genitourinary Cancers Symposium, 2013. Orlando, FL; 2013.Google Scholar
  46. 46.
    Bajorin DF, et al. Preliminary safety, product parameters, and immune response assessments from a phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy (ACI), in patients (pts) with surgically resected HER2+ urothelial cancer (UC) at high risk for recurrence. ASCO meeting abstracts, 2013;31(15_suppl):4547.Google Scholar
  47. 47.
    Kantoff PW et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.PubMedCrossRefGoogle Scholar
  48. 48.
    Inman BA et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109(8):1499–505.PubMedCrossRefGoogle Scholar
  49. 49.
    Thomas Powles, N.J.V., Gregg Daniel Fine, Joseph Paul Eder, Fadi S. Braiteh, Yohann Loriot, Cristina Cruz Zambrano, Joaquim Bellmunt, Howard A. Burris, Siew-leng Melinda Teng, Xiaodong Shen, Hartmut Koeppen, Priti S. Hegde, Daniel S. Chen, Daniel Peter Petrylak. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer in ASCO annual meeting. 2014. Chicago, USA.Google Scholar
  50. 50.
    Grupp SA et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Bochner BH et al. Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst. 1995;87(21):1603–12.PubMedCrossRefGoogle Scholar
  52. 52.
    Bernardini S et al. Serum levels of vascular endothelial growth factor as a prognostic factor in bladder cancer. J Urol. 2001;166(4):1275–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Bellmunt J et al. Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity. Ann Oncol. 2011;22(12):2646–53.PubMedCrossRefGoogle Scholar
  54. 54.
    Gallagher DJ et al. Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response. Eur Urol. 2011;60(2):344–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Necchi A et al. Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial. Lancet Oncol. 2012;13(8):810–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Balar AV et al. Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin Oncol. 2013;31(6):724–30.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Hahn NM et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04–75. J Clin Oncol. 2011;29(12):1525–30.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Richard M. Bambury
    • 1
    Email author
  • Robert B. Sims
    • 1
  • Jonathan E. Rosenberg
    • 1
  1. 1.Department of Genitourinary Medical Oncology, Sidney Kimmel Center for Prostate and Urologic CancersMemorial Sloan Kettering Cancer Center/Weill Cornell Medical CollegeNew YorkUSA

Personalised recommendations