Avelumab Plus Carboplatin-gemcitabine in Urothelial Carcinoma

Summary

Phase II Multicentre, randomized, open-label study to evaluate the safety and efficacy of avelumab with gemcitabine/carboplatin versus gemcitabine/carboplatin alone in patients with unresectable or metastatic urothelial carcinoma (UC) who have not received prior systemic therapy and who are ineligible to receive cisplatin-based therapy.

Timeline

Start

2018-05-17

Primary completion

2022-08-31

Completion

2022-08-31

Publications

• Background Bajorin DF, Dodd PM, Mazumdar M, Fazzari M, McCaffrey JA, Scher HI, Herr H, Higgins G, Boyle MG. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999 Oct;17(10):3173-81. doi: 10.1200/JCO.1999.17.10.3173.
• Background Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010 Dec 15;127(12):2893-917. doi: 10.1002/ijc.25516.
• Background Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010 Mar;46(4):765-81. doi: 10.1016/j.ejca.2009.12.014. Epub 2010 Jan 29.
• Background Witjes JA, Comperat E, Cowan NC, De Santis M, Gakis G, Lebret T, Ribal MJ, Van der Heijden AG, Sherif A; European Association of Urology. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol. 2014 Apr;65(4):778-92. doi: 10.1016/j.eururo.2013.11.046. Epub 2013 Dec 12.
• Background AJCC cancer staging manual. 7th ed. New York: Springer, pp. 497-502.
• Background National Comprehensive Cancer Network (2011) NCCN clinical practice guidelines for bladder cancer. www nccn org.
• Background Bellmunt J, Albiol S. New chemotherapy combinations for advanced bladder cancer. Curr Opin Urol. 2001 Sep;11(5):517-22. doi: 10.1097/00042307-200109000-00011.
• Background Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. doi: 10.1200/JCO.1992.10.7.1066.
• Background Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, Dreicer R, Vogelzang N, Sternberg CN, Bajorin DF, Bellmunt J. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011 Jun 10;29(17):2432-8. doi: 10.1200/JCO.2011.34.8433. Epub 2011 May 9.
• Background De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. doi: 10.1200/JCO.2011.37.3571. Epub 2011 Dec 12.
• Background Dogliotti L, Carteni G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. doi: 10.1016/j.eururo.2006.12.029. Epub 2006 Dec 26.
• Background Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 7;387(10031):1909-20. doi: 10.1016/S0140-6736(16)00561-4. Epub 2016 Mar 4.
• Background Plimack ER, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol 33, 2015 (suppl;abstr 4502).
• Background Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, Curiel TJ, Colon-Otero G, Hamid O, Sanborn RE, O'Donnell PH, Drakaki A, Tan W, Kurland JF, Rebelatto MC, Jin X, Blake-Haskins JA, Gupta A, Segal NH. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol. 2016 Sep 10;34(26):3119-25. doi: 10.1200/JCO.2016.67.9761. Epub 2016 Jun 6.
• Background Galsky M, et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate 275 study. Presented at ESMO 2016 (abstract LBA31_PR).
• Background http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keynote-045-studying-keytruda-pembrolizumab-advanced-bladder-c.
• Background Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Duran I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thastrom A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. doi: 10.1016/S0140-6736(16)32455-2. Epub 2016 Dec 8.
• Background Balar A, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study. Presented at ESMO 2016 (abstract LBA32_PR).
• Background Patel M. R., Ellerton J. A., Infante J. R., et al. Avelumab in patients with metastatic urothelial carcinoma: pooled results from two cohorts of the phase 1b JAVELIN solid tumor trial. Journal of Clinical Oncology. 2017;35(supplement 6S) doi: 10.1200/JCO.2017.35.6_suppl.330. abstract 330.
• Background Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. doi: 10.1200/JCO.2016.71.6795. Epub 2017 Apr 4.
• Background Heery CR, O'Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, Lamping E, Oyelakin I, Marte JL, Lepone LM, Donahue RN, Grenga I, Cuillerot JM, Neuteboom B, Heydebreck AV, Chin K, Schlom J, Gulley JL. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017 May;18(5):587-598. doi: 10.1016/S1470-2045(17)30239-5. Epub 2017 Mar 31.
• Background Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014 Jan;21(1):15-25. doi: 10.1038/cdd.2013.67. Epub 2013 Jun 21.
• Background Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012 Jun 10;30(17):2046-54. doi: 10.1200/JCO.2011.38.4032. Epub 2012 Apr 30.
• Background Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Lu H, Cuillerot JM, Lynch TJ. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013 Jan;24(1):75-83. doi: 10.1093/annonc/mds213. Epub 2012 Aug 2.
• Background Hamilton G, Rath B. Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity. Expert Opin Biol Ther. 2017 Apr;17(4):515-523. doi: 10.1080/14712598.2017.1294156. Epub 2017 Feb 22.
• Background Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.
• Background Rodriguez-Vida A, Bellmunt J. Avelumab for the treatment of urothelial cancer. Expert Rev Anticancer Ther. 2018 May;18(5):421-429. doi: 10.1080/14737140.2018.1448271. Epub 2018 Mar 14.
• Background Rodriguez Vida A et al. Phase II randomized study of first line avelumab with carboplatin-gemcitabine versus carboplatin-gemcitabine alone in patients with metastatic urothelial carcinoma ineligible for cisplatin-based therapy. DOI: 10.1200/JCO.2018.36.15_suppl.TPS4591 Journal of Clinical Oncology 36, no. 15_suppl.
• Results Perez Valderrama B et al. LBA27 - Phase II multicenter, randomized study to evaluate efficacy and safety of avelumab with gemcitabine/carboplatin (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.

Drugs

Indications