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A phase II study of cediranib (AZD 2171) in treatment naive patients with progressive unresectable recurrent or metastatic renal cell carcinoma. A trial of the PMH phase 2 consortium

  • PHASE II STUDIES
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Summary

Background Inhibition of angiogenesis has emerged as an effective therapeutic strategy in metastatic renal cell cancer (mRCC). In this single arm phase 2 study, we evaluated the efficacy and tolerability of cediranib (AZD2171) a potent angiogenesis inhibitor in first line mRCC. Methods Eligible patients who had no prior systemic therapy received cediranib 45 mg orally once daily continuously. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate (ORR plus stable disease (SD) ≥ 4 months), duration of response, progression free survival (PFS), median overall survival (OS), safety and tolerability. Results Between January 2006 and April 2008, 44 patients were accrued. The median age was 62 (range 44–83) and performance status was either 0 (22 patients) or 1 (22 patients). Of the 39 evaluable patients there were 15 (38 %) partial responses (95 % CI: 23–55 %); 18 stable disease (SD) for a clinical benefit rate of 33/39 = 85 % (95 % CI: 69–94 %) and 6 progressive disease. Median PFS was 8.9 months (95 % CI: 5.1–12.9); and median OS was 28.6 months (95 % CI: 18.2–37.3 months). The most frequent grade 3 or higher AEs included hypertension, fatigue, hand-foot syndrome and diarrhea. Conclusions Cediranib demonstrated significant anti-tumour activity in first line, treatment-naive mRCC, with efficacy parameters comparable to the other approved agents (sunitinib and pazopanib) in this setting. The main toxicities were fatigue, diarrhea and hypertension. Based on these encouraging results, further evaluation of cediranib in mRCC at a more tolerable dose of 30 mg daily appears warranted.

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References

  1. Janzen NK, Kim HL, Figlin RA, Belldegrun AS (2003) Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin N Am 30(4):843–852

    Article  Google Scholar 

  2. Belldegrun AS, Klatte T, Shuch B, LaRochelle JC, Miller DC, Said JW, Riggs SB, Zomorodian N, Kabbinavar FF, Dekernion JB, Pantuck AJ (2008) Cancer-specific survival outcomes among patients treated during the cytokine era of kidney cancer (1989–2005): a benchmark for emerging targeted cancer therapies. Cancer 113(9):2457–2463. doi:10.1002/cncr.23851

    Article  PubMed  Google Scholar 

  3. Oudard S, George D, Medioni J, Motzer R (2007) Treatment options in renal cell carcinoma: past, present and future. Ann Oncol Off J Eur Soc Med Oncol / ESMO 18(Suppl 10):x25–x31. doi:10.1093/annonc/mdm411

    Article  Google Scholar 

  4. Coppin C, Kollmannsberger C, Le L, Porzsolt F, Wilt TJ (2011) Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials. BJU Int 108(10):1556–1563. doi:10.1111/j.1464-410X.2011.10629.x

    Article  PubMed  CAS  Google Scholar 

  5. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jurgensmeier JM, Ogilvie DJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65(10):4389–4400. doi:10.1158/0008-5472.CAN-04-4409

    Article  PubMed  CAS  Google Scholar 

  6. Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, Harder J, Blum H, Robertson J, Jurgensmeier JM, Puchalski TA, Young H, Saunders O, Unger C (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol Off J Am Soc Clin Oncol 25(21):3045–3054. doi:10.1200/JCO.2006.07.2066

    Article  CAS  Google Scholar 

  7. Yamamoto N, Tamura T, Yamamoto N, Yamada K, Yamada Y, Nokihara H, Fujiwara Y, Takahashi T, Murakami H, Boku N, Yamazaki K, Puchalski TA, Shin E (2009) Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 64(6):1165–1172. doi:10.1007/s00280-009-0979-8

    Article  PubMed  CAS  Google Scholar 

  8. Tofts PS, Kermode AG (1991) Measurement of the blood–brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn Reson Med Off J Soc Magn Reson Med / Soc Magn Reson Med 17(2):357–367

    Article  CAS  Google Scholar 

  9. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10

    Article  PubMed  CAS  Google Scholar 

  10. 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(2):115–124. doi:10.1056/NEJMoa065044

    Article  PubMed  CAS  Google Scholar 

  11. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, Group TS (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134. doi:10.1056/NEJMoa060655

    Article  PubMed  CAS  Google Scholar 

  12. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V (2010) Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol Off J Am Soc Clin Oncol 28(13):2144–2150. doi:10.1200/JCO.2009.26.7849

    Article  CAS  Google Scholar 

  13. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol Off J Am Soc Clin Oncol 28(6):1061–1068. doi:10.1200/JCO.2009.23.9764

    Article  CAS  Google Scholar 

  14. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ, Global AT (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281. doi:10.1056/NEJMoa066838

    Article  PubMed  CAS  Google Scholar 

  15. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A, Group R-S (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372(9637):449–456. doi:10.1016/S0140-6736(08)61039-9

    Article  PubMed  CAS  Google Scholar 

  16. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10(12):2298–2308. doi:10.1158/1535-7163.MCT-11-0264

    Article  PubMed  CAS  Google Scholar 

  17. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. doi:10.1056/NEJMoa1200694

    Article  PubMed  CAS  Google Scholar 

  18. Sonpavde G, Choueiri TK, Escudier B, Ficarra V, Hutson TE, Mulders PF, Patard JJ, Rini BI, Staehler M, Sternberg CN, Stief CG (2012) Sequencing of agents for metastatic renal cell carcinoma: can we customize therapy? Eur Urol 61(2):307–316. doi:10.1016/j.eururo.2011.10.032

    Article  PubMed  CAS  Google Scholar 

  19. Hotte SJ, Bjarnason GA, Heng DY, Jewett MA, Kapoor A, Kollmannsberger C, Maroun J, Mayhew LA, North S, Reaume MN, Ruether JD, Soulieres D, Venner PM, Winquist EW, Wood L, Yong JH, Saad F (2011) Progression-free survival as a clinical trial endpoint in advanced renal cell carcinoma. Curr Oncol 18(Suppl 2):S11–S19

    PubMed  Google Scholar 

  20. Seidel C, Busch J, Weikert S, Steffens S, Fenner M, Ganser A, Grunwald V (2012) Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma. Eur J Cancer 48(7):1023–1030. doi:10.1016/j.ejca.2012.02.048

    Article  PubMed  CAS  Google Scholar 

  21. Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, Figlin RA, Baum MS, Motzer RJ (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103(9):763–773. doi:10.1093/jnci/djr128

    Article  PubMed  CAS  Google Scholar 

  22. Rini BI, Grunwald V, Fishman MN, Melichar B, Ueda T, Karlov PA, Bair AH, Chen Y, Kim S, Jonasch E (2012) Axitinib for first-line metastatic renal cell carcinoma (mRCC): overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study. J Clin Oncol 30, 2012 (suppl; abstr 4503)

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Acknowledgments

This project was supported by an NIH grant. NCI Contracts N01CM17107, N01CM62203

Conflicts of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Princess Margaret Hospital, Toronto, ON, Canada

    Srikala S. Sridhar, Ian F. Tannock, Masoom A. Haider, Eric X. Chen, Robert Halford, Lisa Wang & Malcolm J. Moore

  2. London Regional Cancer Center, London, ON, Canada

    Mary J. Mackenzie

  3. Juravinski Cancer Center, Hamilton, ON, Canada

    Sebastien J. Hotte & Som D. Mukherjee

  4. BC Cancer Agency, Vancouver, BC, Canada

    Nevin Murray & Christian Kollmannsberger

  5. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    S. Percy Ivy

  6. Princess Margaret Hospital, University Health Network, 522, 610 University Avenue, Toronto, ON, M5G 2M9, Canada

    Srikala S. Sridhar

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  1. Srikala S. Sridhar
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  2. Mary J. Mackenzie
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  3. Sebastien J. Hotte
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Correspondence to Srikala S. Sridhar.

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Presentations

American Society of Clinical Oncology Annual Meeting, Poster Presentation 2007 (Abstract 5093); Poster Discussion ASCO 2008 (Abstract 5047).

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Sridhar, S.S., Mackenzie, M.J., Hotte, S.J. et al. A phase II study of cediranib (AZD 2171) in treatment naive patients with progressive unresectable recurrent or metastatic renal cell carcinoma. A trial of the PMH phase 2 consortium. Invest New Drugs 31, 1008–1015 (2013). https://doi.org/10.1007/s10637-013-9931-1

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