Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: A phase 1/2 study

Journal for ImmunoTherapy of Cancer

Volumn 2, Issue 1, 2014, Pages

  Bhatia, Shailender ^a,l   Curti, Brendan ^b   Ernstoff, Marc S ^c   Gordon, Michael ^d   Heath, Elisabeth I ^e   Miller, Wilson H ^f   Puzanov, Igor ^g   Quinn, David I ^h   Flaig, Thomas W ⁱ   VanVeldhuizen, Peter ^j   Byrnes Blake, Kelly ^l   Freeman, Jeremy A ^l   Bittner, Rachel ^k   Hunder, Naomi ^l   Souza, Sonia ^l   Thompson, John A ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

^b PROVIDENCE PORTLAND MEDICAL CENTER   (United States)

^c DARTMOUTH HITCHCOCK MEDICAL CENTER   (United States)

^d Pinnacle Oncology Hematology   (United States)

^e WAYNE STATE UNIVERSITY   (United States)

^f MCGILL UNIVERSITY   (Canada)

^g VANDERBILT INGRAM CANCER CENTER   (United States)

^h UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

ⁱ UNIVERSITY OF COLORADO CANCER CENTER   (United States)

^j UNIVERSITY OF KANSAS MEDICAL CENTER   (United States)

^k BRISTOL MYERS SQUIBB   (United States)

^l SEATTLE CANCER CARE ALLIANCE   (United States)

more..

Author keywords

Cytokine; Durable response; Immunotherapy; Interleukin 21; Renal cell carcinoma (RCC); Sorafenib; Targeted therapy; Tyrosine kinase inhibitors (TKI); VEGF

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; INTERLEUKIN 2 RECEPTOR ALPHA; RECOMBINANT INTERLEUKIN 21; SORAFENIB; TRIACYLGLYCEROL LIPASE; VASCULOTROPIN;

ALOPECIA; ANTINEOPLASTIC ACTIVITY; ARTHRALGIA; ARTICLE; CHILL; DIARRHEA; DRUG DOSE REDUCTION; DRUG RESPONSE; DRUG SAFETY; ELECTROLYTE DISTURBANCE; FATIGUE; FEVER; HAND FOOT SYNDROME; HEADACHE; HUMAN; HYPERURICEMIA; HYPOKALEMIA; HYPONATREMIA; HYPOPHOSPHATEMIA; INFLUENZA; KIDNEY METASTASIS; LEUKOPENIA; LIMB PAIN; LIVER DISEASE; LYMPHOCYTOPENIA; MAJOR CLINICAL STUDY; MAXIMUM TOLERATED DOSE; NATURAL KILLER T CELL; NAUSEA; NEUTROPENIA; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PRURITUS; RASH; RECOMMENDED DRUG DOSE; THROMBOCYTOPENIA; VOMITING;

EID: 84977111822     PISSN: None     EISSN: 20511426     Source Type: Journal    
DOI: 10.1186/2051-1426-2-2     Document Type: Article

References (52)

1. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010, 28:1061-1068. 10.1200/JCO.2009.23.9764, 20100962.
2. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125-134. 10.1056/NEJMoa060655, 17215530.
3. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007, 370:2103-2111. 10.1016/S0140-6736(07)61904-7, 18156031.
4. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007, 356:2271-2281. 10.1056/NEJMoa066838, 17538086.
5. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008, 372:449-456. 10.1016/S0140-6736(08)61039-9, 18653228.
6. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356:115-124. 10.1056/NEJMoa065044, 17215529.
7. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008, 26:5422-5428. 10.1200/JCO.2008.16.9847, 2651074, 18936475.
8. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995, 13:688-696.
9. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000, 408:57-63. 10.1038/35040504, 11081504.
10. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA. IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol 2004, 173:900-909.
11. Parrish-Novak J, Foster DC, Holly RD, Clegg CH. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J Leukoc Biol 2002, 72:856-863.
12. Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, Pallone F, Monteleone G. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol 2007, 178:732-739.
13. Li Y, Yee C. IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 2008, 111:229-235. 10.1182/blood-2007-05-089375, 2200808, 17921346.
14. Kim-Schulze S, Kim HS, Fan Q, Kim DW, Kaufman HL. Local IL-21 promotes the therapeutic activity of effector T cells by decreasing regulatory T cells within the tumor microenvironment. Mol Ther 2009, 17:380-388. 10.1038/mt.2008.249, 2835064, 19034262.
15. Castermans K, Tabruyn SP, Zeng R, van Beijnum JR, Eppolito C, Leonard WJ, Shrikant PA, Griffioen AW. Angiostatic activity of the antitumor cytokine interleukin-21. Blood 2008, 112:4940-4947. 10.1182/blood-2007-09-113878, 18515660.
16. Di Carlo E, Comes A, Orengo AM, Rosso O, Meazza R, Musiani P, Colombo MP, Ferrini S. IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice. J Immunol 2004, 172:1540-1547.
17. Sondergaard H, Frederiksen KS, Thygesen P, Galsgaard ED, Skak K, Kristjansen PE, Odum N, Kragh M. Interleukin 21 therapy increases the density of tumor infiltrating CD8+ T cells and inhibits the growth of syngeneic tumors. Cancer Immunol Immunother 2007, 56:1417-1428. 10.1007/s00262-007-0285-4, 17285290.
18. Wang G, Tschoi M, Spolski R, Lou Y, Ozaki K, Feng C, Kim G, Leonard WJ, Hwu P. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res 2003, 63:9016-9022.
19. Nakano H, Kishida T, Asada H, Shin-Ya M, Shinomiya T, Imanishi J, Shimada T, Nakai S, Takeuchi M, Hisa Y, Mazda O. Interleukin-21 triggers both cellular and humoral immune responses leading to therapeutic antitumor effects against head and neck squamous cell carcinoma. J Gene Med 2006, 8:90-99. 10.1002/jgm.817, 16097036.
20. Skak K, Kragh M, Hausman D, Smyth MJ, Sivakumar PV. Interleukin 21: combination strategies for cancer therapy. Nat Rev Drug Discov 2008, 7:231-240. 10.1038/nrd2482, 18259184.
21. Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow JW, Moller NP, Skak K, Lundsgaard D, Frederiksen KS, Thygesen P, McArthur GA. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin Cancer Res 2007, 13:3630-3636. 10.1158/1078-0432.CCR-07-0410, 17575227.
22. Thompson JA, Curti BD, Redman BG, Bhatia S, Weber JS, Agarwala SS, Sievers EL, Hughes SD, DeVries TA, Hausman DF. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008, 26:2034-2039. 10.1200/JCO.2007.14.5193, 18347008.
23. Davis ID, Brady B, Kefford RF, Millward M, Cebon J, Skrumsager BK, Mouritzen U, Hansen LT, Skak K, Lundsgaard D, et al. Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: a phase IIa trial. Clin Cancer Res 2009, 15:2123-2129. 10.1158/1078-0432.CCR-08-2663, 19276257.
24. Junghans RP, Waldmann TA. Metabolism of Tac (IL2Ralpha): physiology of cell surface shedding and renal catabolism, and suppression of catabolism by antibody binding. J Exp Med 1996, 183:1587-1602. 10.1084/jem.183.4.1587, 2192498, 8666917.
25. Iguchi M, Matsumoto M, Hojo K, Wada T, Matsuo Y, Arimura A, Abe K. Antitumor efficacy of recombinant human interleukin-2 combined with sorafenib against mouse renal cell carcinoma. Jpn J Clin Oncol 2009, 39:303-309. 10.1093/jjco/hyp021, 19336449.
26. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M, Divino CM, Pan PY, Chen SH. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 2009, 69:2514-2522. 10.1158/0008-5472.CAN-08-4709, 19276342.
27. Desar IM, Jacobs JH, Hulsbergen-Vandekaa CA, Oyen WJ, Mulders PF, van der Graaf WT, Adema GJ, van Herpen CM, de Vries IJ. Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients. Int J Cancer 2011, 129(2):507-512. 10.1002/ijc.25674, 20839259.
28. Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L, Elson P, Garcia J, Dreicer R, Bukowski R. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 2008, 14:6674-6682. 10.1158/1078-0432.CCR-07-5212, 18927310.
29. Sivakumar P, Johnson B, Brasel K, et al. Preclinical evaluation of IL-21 combination therapy with sorafenib and sunitinib in renal cell carcinoma [abstract 266]. EJC Suppl 2006, 4:85.
30. Nguyen MM, Gill IS, Ellison LM. The evolving presentation of renal carcinoma in the United States: trends from the surveillance, epidemiology, and End Results program. J Urol 2006, 176:2397-2400. discussion 2400, 10.1016/j.juro.2006.07.144, 17085111.
31. Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004, 22:454-463.
32. Strumberg D, Awada A, Hirte H, Clark JW, Seeber S, Piccart P, Hofstra E, Voliotis D, Christensen O, Brueckner A, Schwartz B. Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: is rash associated with treatment outcome?. Eur J Cancer 2006, 42:548-556. 10.1016/j.ejca.2005.11.014, 16426838.
33. Frederiksen KS, Lundsgaard D, Freeman JA, Hughes SD, Holm TL, Skrumsager BK, Petri A, Hansen LT, McArthur GA, Davis ID, Skak K. IL-21 induces in vivo immune activation of NK cells and CD8(+) T cells in patients with metastatic melanoma and renal cell carcinoma. Cancer Immunol Immunother 2008, 57:1439-1449. 10.1007/s00262-008-0479-4, 2491425, 18286285.
34. Sabatino M, Kim-Schulze S, Panelli MC, Stroncek D, Wang E, Taback B, Kim DW, Deraffele G, Pos Z, Marincola FM, Kaufman HL. Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol 2009, 27:2645-2652. 10.1200/JCO.2008.19.1106, 2689845, 19364969.
35. Porta C, Paglino C, De Amici M, Quaglini S, Sacchi L, Imarisio I, Canipari C. Predictive value of baseline serum vascular endothelial growth factor and neutrophil gelatinase-associated lipocalin in advanced kidney cancer patients receiving sunitinib. Kidney Int 2010, 77:809-815. 10.1038/ki.2009.552, 20147887.
36. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 2009, 27:1280-1289. 10.1200/JCO.2008.19.3342, 19171708.
37. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011, 378:1931-1939. 10.1016/S0140-6736(11)61613-9, 22056247.
38. Cho DC, Puzanov I, Regan MM, Schwarzberg T, Seery V, Lee MY, Liu V, Bhatt R, Koon H, Mier JW, et al. Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma. J Immunother 2009, 32:181-185. 10.1097/CJI.0b013e3181952b1d, 19238017.
39. Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer 2009, 115:61-67. 10.1002/cncr.24009, 19051290.
40. Di Lorenzo G, Carteni G, Autorino R, Bruni G, Tudini M, Rizzo M, Aieta M, Gonnella A, Rescigno P, Perdona S, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol 2009, 27:4469-4474. 10.1200/JCO.2009.22.6480, 19652053.
41. Garcia JA, Hutson TE, Elson P, Cowey CL, Gilligan T, Nemec C, Dreicer R, Bukowski RM, Rini BI. Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab. Cancer 2010, 116:5383-5390. 10.1002/cncr.25327, 20806321.
42. Porta C, Procopio G, Carteni G, Sabbatini R, Bearz A, Chiappino I, Ruggeri EM, Re GL, Ricotta R, Zustovich F, et al. Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma (RCC): an Italian multicentre retrospective analysis of 189 patient cases. BJU Int 2011, 108:E250-E257. 10.1111/j.1464-410X.2011.10186.x, 21599821.
43. Herrmann E, Marschner N, Grimm MO, Ohlmann CH, Hutzschenreuter U, Overkamp F, Groschek M, Blumenstengel K, Puhse G, Steiner T. Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma. World J Urol 2011, 29:361-366. 10.1007/s00345-011-0673-4, 21461939.
44. Grunwald V, Desar IM, Haanen J, Fiedler W, Mouritzen U, Olsen MW, van Herpen CM. A phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC). Acta Oncol 2011, 50:121-126. 10.3109/0284186X.2010.509104, 21174612.
45. Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, Fischer P, Ronnen E, Ishill N, Patil S, Motzer RJ. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2009, 27:1432-1439. 10.1200/JCO.2008.19.0108, 3655420, 19224847.
46. Motzer RJ, Hudes G, Wilding G, Schwartz LH, Hariharan S, Kempin S, Fayyad R, Figlin RA. Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 2009, 7:28-33. 10.3816/CGC.2009.n.005, 3394091, 19213665.
47. Gollob JA, Rathmell WK, Richmond TM, Marino CB, Miller EK, Grigson G, Watkins C, Gu L, Peterson BL, Wright JJ. Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol 2007, 25:3288-3295. 10.1200/JCO.2007.10.8613, 17664476.
48. Ryan CW, Goldman BH, Lara PN, Mack PC, Beer TM, Tangen CM, Lemmon D, Pan CX, Drabkin HA, Crawford ED. Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: a phase II study of the Southwest Oncology Group. J Clin Oncol 2007, 25:3296-3301. 10.1200/JCO.2007.11.1047, 17664477.
49. Jonasch E, Corn P, Pagliaro LC, Warneke CL, Johnson MM, Tamboli P, Ng C, Aparicio A, Ashe RG, Wright JJ, Tannir NM. Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis. Cancer 2010, 116:57-65.
50. Krusch M, Salih J, Schlicke M, Baessler T, Kampa KM, Mayer F, Salih HR. The kinase inhibitors sunitinib and sorafenib differentially affect NK cell antitumor reactivity in vitro. J Immunol 2009, 183:8286-8294. 10.4049/jimmunol.0902404, 20007592.
51. Hipp MM, Hilf N, Walter S, Werth D, Brauer KM, Radsak MP, Weinschenk T, Singh-Jasuja H, Brossart P. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood 2008, 111:5610-5620. 10.1182/blood-2007-02-075945, 18310500.
52. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000, 92:205-216. 10.1093/jnci/92.3.205, 10655437.