Investigational New Drugs

, Volume 37, Issue 6, pp 1231–1238 | Cite as

Phase II trial of continuous treatment with sunitinib in patients with high-risk (BCG-refractory) non-muscle invasive bladder cancer

  • Haris Zahoor
  • Maria C. Mir
  • Pedro C. Barata
  • Andrew J. Stephenson
  • Steven C. Campbell
  • Amr Fergany
  • Robert Dreicer
  • Jorge A. GarciaEmail author


Purpose Sunitinib is a vascular endothelial growth factor receptor (VEGFR) inhibitor with antitumor activity against bladder cancer. We hypothesized that treatment with sunitinib may decrease progression or recurrence in non-muscle invasive bladder cancer (NMIBC) refractory to intra-vesical BCG. Patients and Methods This is a single-arm phase II study of sunitinib in patients (pts) with NMIBC who progressed after BCG. Treatment included sunitinib 37.5 g daily for 12 weeks followed by 12± 2-week cystoscopy and surveillance for one year. The primary endpoint was the complete response rate at 12 months. Secondary endpoints included recurrence free survival (RFS), progression free survival (PFS), overall survival (OS), and safety of sunitinib. Correlative studies on effects of sunitinib on myeloid derived suppressor cells (MDSC) and humoral immune responses were also performed. This trial was registered on, number NCT01118351. Results Between June 2011 and September 2011, 15/19 pts. completed 12 weeks of therapy. The remaining 4 pts. had treatment related adverse events leading to discontinuation of sunitinib with one patient withdrawing consent. On the 12-week cystoscopy, 44% (8/18) of the pts. showed remission, 50% (9/18) progression and 1/18 recurrence. Overall, 22% (4/18) of pts. remained free of progression for >12 months. Grade (G) 4 toxicities were noted in 2 pts. (anemia and thrombocytopenia) while G3 were noted in 58%. Sunitinib resulted in reversal of MDSC mediated immunosuppression. Conclusions In NMIBC refractory to BCG, treatment with sunitinib was safe but not associated with improved clinical outcomes. The immune effects of sunitinib deserve further investigation.


Sunitinib Non-muscle invasive bladder cancer BCG-refractory Angiogenesis MDSC 


Authors’ contributions

HZ contributed to the data acquisition, drafting and final revision of the manuscript. MCM participated in data acquisition and final revision of the manuscript. PCB participated in data acquisition and final revision of the manuscript. AJS participated in data acquisition and final revision of the manuscript. SCC participated in data acquisition and final revision of the manuscript. RD participated in data acquisition and final revision of the manuscript. JAG contributed to the conception and coordination of the study, data acquisition, drafting and final revision of the manuscript. All authors read and approved the manuscript.


The work was supported by the Pfizer Inc.

Compliance with ethical standards

Conflicts of interest

HZ declares that he has no conflict of interest. MCM declares that he has no conflict of interest. PCB declares that he has no conflict of interest. AJS declares that he has no conflict of interest. SCC declares that he has no conflict of interest. AF declares that he has no conflict of interest. RD has served as a consultant for Astra Zeneca, Janssen, Pfizer, Lilly and Astellas. The other authors declare no competing interests directly related to this manuscript. JAG has honoraria from Bayer, Sanofi, Pfizer, Genentech, Janssen, Eisai and Exelixis.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30Google Scholar
  2. 2.
    Pasin E, Josephson DY, Mitra AP, Cote RJ, Stein JP (2008) Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history. Rev Urol 10:31–43PubMedPubMedCentralGoogle Scholar
  3. 3.
    Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK, Clark PE, Downs TM, Efstathiou JA, Flaig TW, Friedlander T, Greenberg RE, Guru KA, Hahn N, Herr HW, Hoimes C, Inman BA, Jimbo M, Kader AK, Lele SM, Meeks JJ, Michalski J, Montgomery JS, Pagliaro LC, Pal SK, Patterson A, Plimack ER, Pohar KS, Porter MP, Preston MA, Sexton WJ, Siefker-Radtke AO, Sonpavde G, Tward J, Wile G, Dwyer MA, Gurski LA (2017) Bladder Cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 15:1240–1267Google Scholar
  4. 4.
    Smith JA Jr, Labasky RF, Cockett AT et al (1999) Bladder cancer clinical guidelines panel summary report on the management of nonmuscle invasive bladder cancer (stages ta, T1 and TIS). The American Urological Association. J Urol 162:1697–1701PubMedGoogle Scholar
  5. 5.
    Soloway MS, Sofer M, Vaidya A (2002) Contemporary management of stage T1 transitional cell carcinoma of the bladder. J Urol 167:1573–1583PubMedGoogle Scholar
  6. 6.
    Thalmann GN, Markwalder R, Shahin O et al (2004) Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy? J Urol 172:70–75PubMedGoogle Scholar
  7. 7.
    Lamm DL, Griffith JG (1992) Intravesical therapy: does it affect the natural history of superficial bladder cancer? Semin Urol 10:39–44PubMedGoogle Scholar
  8. 8.
    Herr HW, Sogani PC (2001) Does early cystectomy improve the survival of patients with high risk superficial bladder tumors? J Urol 166:1296–1299PubMedGoogle Scholar
  9. 9.
    Shabsigh A, Korets R, Vora KC, Brooks CM, Cronin AM, Savage C, Raj G, Bochner BH, Dalbagni G, Herr HW, Donat SM (2009) Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 55:164–174PubMedGoogle Scholar
  10. 10.
    Bradley DA, Dunn R, Nanus D, Stadler W, Dreicer R, Rosenberg J, Smith DC, Hussain M (2007) Randomized, double-blind, placebo-controlled phase II trial of maintenance sunitinib versus placebo after chemotherapy for patients with advanced urothelial carcinoma: scientific rationale and study design. Clin Genitourin Cancer 5:460–463PubMedGoogle Scholar
  11. 11.
    Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF, Senger DR (1993) Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 143:1255–1262PubMedPubMedCentralGoogle Scholar
  12. 12.
    Sonpavde G, Jian W, Liu H, Wu MF, Shen SS, Lerner SP (2009) Sunitinib malate is active against human urothelial carcinoma and enhances the activity of cisplatin in a preclinical model. Urol Oncol 27:391–399PubMedGoogle Scholar
  13. 13.
    Gallagher DJ, Milowsky MI, Gerst SR, Ishill N, Riches J, Regazzi A, Boyle MG, Trout A, Flaherty AM, Bajorin DF (2010) Phase II study of sunitinib in patients with metastatic urothelial cancer. J Clin Oncol 28:1373–1379PubMedGoogle Scholar
  14. 14.
    Bellmunt J, Gonzalez-Larriba JL, Prior C, Maroto P, Carles J, Castellano D, Mellado B, Gallardo E, Perez-Gracia JL, Aguilar G, Villanueva X, Albanell J, Calvo A (2011) 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 22:2646–2653PubMedGoogle Scholar
  15. 15.
    Harshman L, Srinivas S (2008) Continuous daily dosing of sunitinib in patients with metastatic renal cell cancer. Onkologie 31:432–433PubMedGoogle Scholar
  16. 16.
    Escudier B, Roigas J, Gillessen S, Harmenberg U, Srinivas S, Mulder SF, Fountzilas G, Peschel C, Flodgren P, Maneval EC, Chen I, Vogelzang NJ (2009) Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol 27:4068–4075PubMedGoogle Scholar
  17. 17.
    Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, Hu G, Sun Y (2015) New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med 13:45PubMedPubMedCentralGoogle Scholar
  18. 18.
    Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15:2148–2157PubMedGoogle Scholar
  19. 19.
    Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338PubMedGoogle Scholar
  20. 20.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124PubMedGoogle Scholar
  21. 21.
    Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513PubMedGoogle Scholar
  22. 22.
    Motzer RJ, Jonasch E, Agarwal N, Bhayani S, Bro WP, Chang SS, Choueiri TK, Costello BA, Derweesh IH, Fishman M, Gallagher TH, Gore JL, Hancock SL, Harrison MR, Kim W, Kyriakopoulos C, LaGrange C, Lam ET, Lau C, Michaelson MD, Olencki T, Pierorazio PM, Plimack ER, Redman BG, Shuch B, Somer B, Sonpavde G, Sosman J, Dwyer M, Kumar R (2016) Clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw 15(6):804-834. PubMedGoogle Scholar
  23. 23.
    Grivas PD, Daignault S, Tagawa ST, Nanus DM, Stadler WM, Dreicer R, Kohli M, Petrylak DP, Vaughn DJ, Bylow KA, Wong SG, Sottnik JL, Keller ET, al-Hawary M, Smith DC, Hussain M (2014) Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma. Cancer 120:692–701PubMedGoogle Scholar
  24. 24.
    Izawa JI, Slaton JW, Kedar D, Karashima T, Perrotte P, Czerniak B, Grossman HB, Dinney CP (2001) Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder. Oncol Rep 8:9–15PubMedGoogle Scholar
  25. 25.
    Bochner BH, Cote RJ, Weidner N, Groshen S, Chen SC, Skinner DG, Nichols PW (1995) Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst 87:1603–1612PubMedGoogle Scholar
  26. 26.
    Canoglu A, Gogus C, Beduk Y et al (2004) Microvessel density as a prognostic marker in bladder carcinoma: correlation with tumor grade, stage and prognosis. Int Urol Nephrol 36:401–405PubMedGoogle Scholar
  27. 27.
    Dickinson AJ, Fox SB, Persad RA et al (1994) Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 74:762–766PubMedGoogle Scholar
  28. 28.
    Donmez G, Sullu Y, Baris S, Yildiz L, Aydin O, Karagoz F, Kandemir B (2009) Vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and thrombospondin-1 (TSP-1) expression in urothelial carcinomas. Pathol Res Pract 205:854–857PubMedGoogle Scholar
  29. 29.
    Goddard JC, Sutton CD, Furness PN, O'Byrne KJ, Kockelbergh RC (2003) Microvessel density at presentation predicts subsequent muscle invasion in superficial bladder cancer. Clin Cancer Res 9:2583–2586PubMedGoogle Scholar
  30. 30.
    Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F (2005) Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502–3508PubMedGoogle Scholar
  31. 31.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550PubMedGoogle Scholar
  32. 32.
    Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedGoogle Scholar
  33. 33.
    Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91:1071–1121PubMedPubMedCentralGoogle Scholar
  34. 34.
    Gemcitabine Hydrochloride and Cisplatin With or Without Bevacizumab in Treating Patients With Advanced Urinary Tract Cancer. Available at: [Last accessed August 25, 2018]
  35. 35.
    Gopalakrishnan D, Koshkin VS, Ornstein MC, Papatsoris A, Grivas P (2018) Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook. Ther Clin Risk Manag 14:1019–1040PubMedPubMedCentralGoogle Scholar
  36. 36.
    Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. N Engl J Med 335:865–875PubMedGoogle Scholar
  37. 37.
    Lamiell JM, Salazar FG, von Hsia YE (1989) Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 68:1–29Google Scholar
  38. 38.
    Latif F, Tory K, Gnarra J, Yao M, Duh F, Orcutt M, Stackhouse T, Kuzmin I, Modi W, Geil L et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320PubMedGoogle Scholar
  39. 39.
    Ohki S, Shibata M, Gonda K et al (2012) Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoproteinemia in patients with cancer. Oncol Rep 28:453–458PubMedGoogle Scholar
  40. 40.
    Kusmartsev S, Gabrilovich DI (2006) Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55:237–245PubMedGoogle Scholar
  41. 41.
    George DJ, Kaelin WG Jr (2003) The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med 349:419–421PubMedGoogle Scholar
  42. 42.
    Rini BI, Campbell SC, Escudier B (2009) Renal cell carcinoma. Lancet 373:1119–1132PubMedGoogle Scholar
  43. 43.
    Ping SY, Wu CL, Yu DS (2010) Sunitinib can enhance BCG mediated cytotoxicity to transitional cell carcinoma through apoptosis pathway. Urol OncolGoogle Scholar
  44. 44.
    Alexander M, Helfand CTL, Hafez K, Hussain M, Liebert M, Daignault S, Montgomery JS, Miller DC, Drnek L, Hollenbeck BK, Weizer AZ (2015) Phase II clinical trial of intravesical bacillus Calmette-Guerin (BCG) followed by sunitinib for the treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC). J Clin Oncol 33(suppl 7; abstr 293):2015Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Haris Zahoor
    • 1
  • Maria C. Mir
    • 2
  • Pedro C. Barata
    • 3
  • Andrew J. Stephenson
    • 4
  • Steven C. Campbell
    • 4
  • Amr Fergany
    • 4
  • Robert Dreicer
    • 5
  • Jorge A. Garcia
    • 4
    • 6
    Email author
  1. 1.Division of Medical Oncology, USC Norris Comprehensive Cancer CenterKeck School of MedicineLos AngelesUSA
  2. 2.Urology DepartmentIMED Valencia HospitalValenciaSpain
  3. 3.Department of Internal Medicine, Section of Hematology and Medical OncologyTulane Medical SchoolNew OrleansUSA
  4. 4.Cleveland ClinicGlickman Urological and Kidney InstituteClevelandUSA
  5. 5.Division Hematology/OncologyUniversity of Virginia School of MedicineCharlottesvilleUSA
  6. 6.Department of Solid Tumor Oncology and UrologyCleveland Clinic Taussig Cancer InstituteClevelandUSA

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