Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma

Summary

This is a phase I/II open-label study designed to evaluate the combination of pembrolizumab and cabozantinib in subjects with locally advanced, recurrent, or metastatic renal cell carcinoma. Sequential dose escalation of cabozantinib with standard dose pembrolizumab will occur in the phase I dose escalation part of the study to determine the recommended phase 2 dose (RP2D). Subsequently, subjects will receive cabozantinib at the RP2D in combination with pembrolizumab in the phase II dose expansion part of the study.

Timeline

Start

2017-09-28

Primary completion

2022-12-14

Completion

2024-02-16

Publications

• Background Gunturi A, McDermott DF. Potential of new therapies like anti-PD1 in kidney cancer. Curr Treat Options Oncol. 2014 Mar;15(1):137-46. doi: 10.1007/s11864-013-0268-y.
• Background Philips GK, Atkins MB. New agents and new targets for renal cell carcinoma. Am Soc Clin Oncol Educ Book. 2014:e222-7. doi: 10.14694/EdBook_AM.2014.34.e222.
• Background Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. Immunotherapy. 2016;8(3):299-313. doi: 10.2217/imt.15.126. Epub 2016 Feb 11.
• Background Massari F, Santoni M, Ciccarese C, Santini D, Alfieri S, Martignoni G, Brunelli M, Piva F, Berardi R, Montironi R, Porta C, Cascinu S, Tortora G. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev. 2015 Feb;41(2):114-21. doi: 10.1016/j.ctrv.2014.12.013. Epub 2015 Jan 6.
• Background Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. doi: 10.1056/NEJMoa1510665. Epub 2015 Sep 25.
• Background 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. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009 Mar 15;15(6):2148-57. doi: 10.1158/1078-0432.CCR-08-1332. Epub 2009 Mar 10.
• Background Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J, Sandoval F, Quintin-Colonna F, Lacerda K, Karadimou A, Badoual C, Tedgui A, Fridman WH, Oudard S. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev. 2011 Mar;30(1):83-95. doi: 10.1007/s10555-011-9281-4.
• Background Terme M, Colussi O, Marcheteau E, Tanchot C, Tartour E, Taieb J. Modulation of immunity by antiangiogenic molecules in cancer. Clin Dev Immunol. 2012;2012:492920. doi: 10.1155/2012/492920. Epub 2012 Dec 24.
• Background Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, Zinzindohoue F, Yagita H, Tartour E, Taieb J, Terme M. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015 Feb 9;212(2):139-48. doi: 10.1084/jem.20140559. Epub 2015 Jan 19.
• Background Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011 Jun;10(6):417-27. doi: 10.1038/nrd3455.
• Background Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Mukeria A, Holcatova I, Schmidt LS, Toro JR, Karami S, Hung R, Gerard GF, Linehan WM, Merino M, Zbar B, Boffetta P, Brennan P, Rothman N, Chow WH, Waldman FM, Moore LE. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008 Aug 1;14(15):4726-34. doi: 10.1158/1078-0432.CCR-07-4921.
• Background Gibney GT, Aziz SA, Camp RL, Conrad P, Schwartz BE, Chen CR, Kelly WK, Kluger HM. c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol. 2013 Feb;24(2):343-349. doi: 10.1093/annonc/mds463. Epub 2012 Sep 28.
• Background Mukai S, Yorita K, Kawagoe Y, Katayama Y, Nakahara K, Kamibeppu T, Sugie S, Tukino H, Kamoto T, Kataoka H. Matriptase and MET are prominently expressed at the site of bone metastasis in renal cell carcinoma: immunohistochemical analysis. Hum Cell. 2015 Jan;28(1):44-50. doi: 10.1007/s13577-014-0101-3. Epub 2014 Sep 4.
• Background Schiefer AI, Mesteri I, Berghoff AS, Haitel A, Schmidinger M, Preusser M, Birner P. Evaluation of tyrosine kinase receptors in brain metastases of clear cell renal cell carcinoma reveals cMet as a negative prognostic factor. Histopathology. 2015 Dec;67(6):799-805. doi: 10.1111/his.12709. Epub 2015 Jun 7.
• Background Sutherland DE, Morrow CE, Florack G, Kretschmer GJ, Baumgartner D, Matas AJ, Najarian JS. Cold storage preservation of islet and pancreas grafts as assessed by in vivo function after transplantation to diabetic hosts. Cryobiology. 1983 Apr;20(2):138-50. doi: 10.1016/0011-2240(83)90003-2. No abstract available.
• Background Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol. 2017 Feb 20;35(6):591-597. doi: 10.1200/JCO.2016.70.7398. Epub 2016 Nov 14.
• Background Harshman LC, Choueiri TK. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013 Jul-Aug;19(4):316-23. doi: 10.1097/PPO.0b013e31829e3c9a.
• Background Choueiri TK, Pal SK, McDermott DF, Morrissey S, Ferguson KC, Holland J, Kaelin WG, Dutcher JP. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol. 2014 Aug;25(8):1603-8. doi: 10.1093/annonc/mdu184. Epub 2014 May 14.
• Kessler ER, Callihan E, Hu J, Eule C, Srivastava G, Kemme DJ, Iruku P, Rana V, Moore J, Schuster SR, Amirault M, Flaig TW, Lam ET. A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma. Cancer Res Commun. 2023 Jun 8;3(6):1004-1012. doi: 10.1158/2767-9764.CRC-23-0060. eCollection 2023 Jun.

Drugs

Indications