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Phase I/II study of everolimus combined with mFOLFOX-6 and bevacizumab for first–line treatment of metastatic colorectal cancer

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Summary

Background This phase I/II trial evaluated toxicity and antitumor activity of everolimus plus mFOLFOX6 + bevacizumab for first-line treatment of metastatic colorectal cancer (mCRC). Methods A phase I, modified 3 + 3 Fibonacci schema determined the maximum tolerated dose (MTD) of everolimus, followed by phase II dose expansion. The phase II primary objective was progression-free survival at 6 months (PFS-6 m). Results The everolimus MTD was 10 mg daily with mFOLFOX6 + bevacizumab based on safety from phase I (n = 22). Twenty-five patients were treated in the phase II at 10 mg everolimus daily. Frequent grade 3–4 adverse events were neutropenia (64%), leukopenia (28%) and hypokalemia (26%). Grade 2 stomatitis was observed in 62% of patients. Two dose-limiting toxicities were observed with one attributed to everolimus 10 mg daily (grade 3 diarrhea, hypokalemia, and anorexia) and grade 3 coronary vasospasm attributed to fluorouracil. The objective response rate was 53% and was higher (86%) in those with PTEN deficiency. PFS-6 m was 96% (95% CI 89–99.9%) at the MTD (n = 35). The everolimus recommended phase II dose of this regimen is 7.5 mg daily due to frequent stomatitis and dose reductions. Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC. Further studies are warranted in PTEN deficiency.

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References

  1. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30(2):193–204. https://doi.org/10.1016/j.ctrv.2003.07.007

    Article  CAS  PubMed  Google Scholar 

  2. Mukohara T (2015) PI3K mutations in breast cancer: prognostic and therapeutic implications. Breast Cancer (Dove Med Press) 7:111–123. https://doi.org/10.2147/BCTT.S60696

    Article  CAS  Google Scholar 

  3. Garrido-Laguna I, Hong DS, Janku F, Nguyen LM, Falchook GS, Fu S, Wheler JJ, Luthra R, Naing A, Wang X, Kurzrock R (2012) KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors. PLoS One 7(5):e38033. https://doi.org/10.1371/journal.pone.0038033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cancer Genome Atlas Research N, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, Levine DA (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497(7447):67–73. https://doi.org/10.1038/nature12113

    Article  CAS  Google Scholar 

  5. Bardelli A, Siena S (2010) Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 28(7):1254–1261. https://doi.org/10.1200/JCO.2009.24.6116

    Article  CAS  Google Scholar 

  6. Kim A, Lee JE, Lee SS, Kim C, Lee SJ, Jang WS, Park S (2013) Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP-BEZ235, a dual PI3K/MTOR inhibitor, in regulating the PI3K/MTOR pathway in colorectal cancer. Int J Cancer 133(4):984–996. https://doi.org/10.1002/ijc.28073

    Article  CAS  PubMed  Google Scholar 

  7. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554. https://doi.org/10.1126/science.1096502

    Article  CAS  PubMed  Google Scholar 

  8. Barault L, Veyrie N, Jooste V, Lecorre D, Chapusot C, Ferraz JM, Lievre A, Cortet M, Bouvier AM, Rat P, Roignot P, Faivre J, Laurent-Puig P, Piard F (2008) Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer 122(10):2255–2259. https://doi.org/10.1002/ijc.23388

    Article  CAS  PubMed  Google Scholar 

  9. Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, Fu S, Falchook GS, Hong DS, Garrido-Laguna I, Luthra R, Lee JJ, Lu KH, Kurzrock R (2012) PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol Off J Am Soc Clin Oncol 30(8):777–782. https://doi.org/10.1200/JCO.2011.36.1196

    Article  CAS  Google Scholar 

  10. Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ, Baker SJ, Ellenson LH (2006) PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin Cancer Res 12(20 Pt 1):5932–5935. https://doi.org/10.1158/1078-0432.CCR-06-1375

    Article  CAS  PubMed  Google Scholar 

  11. Janku F, Hong DS, Fu S, Piha-Paul SA, Naing A, Falchook GS, Tsimberidou AM, Stepanek VM, Moulder SL, Lee JJ, Luthra R, Zinner RG, Broaddus RR, Wheler JJ, Kurzrock R (2014) Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors. Cell Rep 6(2):377–387. https://doi.org/10.1016/j.celrep.2013.12.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, Russo M, Cancelliere C, Zecchin D, Mazzucchelli L, Sasazuki T, Shirasawa S, Geuna M, Frattini M, Baselga J, Gallicchio M, Biffo S, Bardelli A (2010) Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 120(8):2858–2866. https://doi.org/10.1172/JCI37539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Ramon y Cajal S, Jones S, Vidal L, Shand N, Macarulla T, Ramos FJ, Dimitrijevic S, Zoellner U, Tang P, Stumm M, Lane HA, Lebwohl D, Baselga J (2008) Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol Off J Am Soc Clin Oncol 26(10):1603–1610. https://doi.org/10.1200/JCO.2007.14.5482

    Article  CAS  Google Scholar 

  14. O'Donnell A, Faivre S, Burris HA 3rd, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brock C, Jones S, Raymond E, Judson I (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol Off J Am Soc Clin Oncol 26(10):1588–1595. https://doi.org/10.1200/JCO.2007.14.0988

    Article  CAS  Google Scholar 

  15. Gold PJ ID, Arthur J, et al. (2008) Phase II trial of RAD001 in patients with refractory metastatic colorectal cancer. J clinical Oncol 27 (15s):[abstract513]

  16. Ng K, Tabernero J, Hwang J, Bajetta E, Sharma S, Del Prete SA, Arrowsmith ER, Ryan DP, Sedova M, Jin J, Malek K, Fuchs CS (2013) Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. Clinical cancer research: an official journal of the American Association for Cancer Research 19(14):3987–3995. https://doi.org/10.1158/1078-0432.CCR-13-0027

    Article  CAS  Google Scholar 

  17. Harzstark AL, Small EJ, Weinberg VK, Sun J, Ryan CJ, Lin AM, Fong L, Brocks DR, Rosenberg JE (2011) A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma. Cancer 117(18):4194–4200. https://doi.org/10.1002/cncr.25931

    Article  CAS  PubMed  Google Scholar 

  18. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) 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 Journal of the National Cancer Institute 92(3):205–216. https://doi.org/10.1093/jnci/92.3.205

    Article  CAS  PubMed  Google Scholar 

  19. Longo DL, Duffey PL, DeVita VT Jr, Wesley MN, Hubbard SM, Young RC (1991) The calculation of actual or received dose intensity: a comparison of published methods. J Clin Oncol Off J Am Soc Clin Oncol 9(11):2042–2051. https://doi.org/10.1200/JCO.1991.9.11.2042

    Article  CAS  Google Scholar 

  20. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol Off J Am Soc Clin Oncol 26(12):2013–2019. https://doi.org/10.1200/JCO.2007.14.9930

    Article  CAS  Google Scholar 

  21. Garg K, Broaddus RR, Soslow RA, Urbauer DL, Levine DA, Djordjevic B (2012) Pathologic scoring of PTEN immunohistochemistry in endometrial carcinoma is highly reproducible. Int J Gynecol Pathol 31(1):48–56. https://doi.org/10.1097/PGP.0b013e3182230d00

    Article  PubMed  PubMed Central  Google Scholar 

  22. Shahda S YM, Picus J, et al. (2011) Phase I study of everolimus (RAD001) with irinotecan and cetuximab in second-line metastatic colorectal cancer: Hoosier oncology group GI05-102- final report. J clinical Oncol 29s:[abstract 3587]

  23. Townsend AR PL, Hardingham J, et al. (2011) A phase Ib/II study of second-line therapy with panitumumab, irinotecan, and everolimus in metastatic colorectal cancer with KRAS wild type. J clinical Oncol 29s:[abstract TPS162]

  24. Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP (2006) PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442(7104):779–785. https://doi.org/10.1038/nature05029

    Article  CAS  PubMed  Google Scholar 

  25. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9–22. https://doi.org/10.1016/j.ccr.2007.05.008

    Article  CAS  PubMed  Google Scholar 

  26. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22(20):7004–7014. https://doi.org/10.1128/MCB.22.20.7004-7014.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bullock KE, Hurwitz HI, Uronis HE, Morse MA, Blobe GC, Hsu SD, Zafar SY, Nixon AB, Howard LA, Bendell JC (2009) Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC). J Clin Oncol 27(15_suppl):4080–4080. https://doi.org/10.1200/jco.2009.27.15_suppl.4080

    Article  Google Scholar 

  28. Altomare I, Bendell JC, Bullock KE, Uronis HE, Morse MA, Hsu SD, Zafar SY, Blobe GC, Pang H, Honeycutt W, Sutton L, Hurwitz HI (2011) A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer. Oncologist 16(8):1131–1137. https://doi.org/10.1634/theoncologist.2011-0078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wolpin BM, Ng K, Zhu AX, Abrams T, Enzinger PC, McCleary NJ, Schrag D, Kwak EL, Allen JN, Bhargava P, Chan JA, Goessling W, Blaszkowsky LS, Supko JG, Elliot M, Sato K, Regan E, Meyerhardt JA, Fuchs CS (2013) Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer. Oncologist 18(4):377–378. https://doi.org/10.1634/theoncologist.2012-0378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rugo HS, Hortobagyi GN, Yao J, Pavel M, Ravaud A, Franz D, Ringeisen F, Gallo J, Rouyrre N, Anak O, Motzer R (2016) Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy. Ann Oncol 27(3):519–525. https://doi.org/10.1093/annonc/mdv595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rugo H SL, Beck J, et al (2016) Prevention of everolimus/exemestane stomatitis in postmenopausal women with hormone receptor–positive metastatic breast cancer using a dexamethasone-based mouthwash: results of the SWISH trial. Abstract MASCC-0638. MASCC/ISOO International Symposium on Supportive Care in Cancer Presented June 23, 2016 24 (1):1–249. https://doi.org/10.1007/s00520-016-3209-z

  32. Rugo HS, Beck JT, Glaspy JA, Peguero JA, Pluard TJ, Dhillon N, Hwang LC, Nangia CS, Mayer IA, Meiller TF, Chambers MS, Warsi G, Sweetman RW, Sabo JR, Seneviratne L (2016) Prevention of everolimus/exemestane (EVE/EXE) stomatitis in postmenopausal (PM) women with hormone receptor-positive (HR+) metastatic breast cancer (MBC) using a dexamethasone-based mouthwash (MW): results of the SWISH trial. Journal of Clinical Oncology 34(26_suppl):189–189. https://doi.org/10.1200/jco.2016.34.26_suppl.189

    Article  Google Scholar 

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Funding

This study was funded by Novartis Pharmaceuticals and the Huntsman Cancer Institute. clinical trial NCT01047293.

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Authors and Affiliations

  1. Department of Internal Medicine (Division of Oncology), Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA

    G. Weldon Gilcrease, John Weis, Jonathan Whisenant, Nicole Orgain & Ignacio Garrido-Laguna

  2. Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, MN, USA

    David D. Stenehjem

  3. Department of Research Compliance: Huntsman Cancer Institute, Salt Lake City, UT, USA

    Mark L. Wade & Kelli Thorne

  4. Medical Affairs, Foundation Medicine, Cambridge, MA, USA

    Kimberly McGregor

  5. Huntsman Intermountain Cancer Care Program, Salt Lake City, UT, USA

    Jonathan Whisenant

  6. Department of Internal Medicine (Epidemiology), University of Utah, Salt Lake City, UT, USA

    Kenneth M. Boucher

  7. Division Clinical Sciences, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA

    Sunil Sharma

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  1. G. Weldon Gilcrease
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Correspondence to G. Weldon Gilcrease.

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Conflict of interest

Sunil Sharma received research support from Novartis Pharmaceuticals and has served on Novartis Pharmaceuticals advisory boards. All other authors have no financial interests to disclose surrounding this manuscript.

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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.

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

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Weldon Gilcrease, G., Stenehjem, D.D., Wade, M.L. et al. Phase I/II study of everolimus combined with mFOLFOX-6 and bevacizumab for first–line treatment of metastatic colorectal cancer. Invest New Drugs 37, 482–489 (2019). https://doi.org/10.1007/s10637-018-0645-2

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