Phase i and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies

Investigational New Drugs

Volumn 30, Issue 4, 2012, Pages 1557-1565

  Deenen, Maarten J ^a   Klümpen, Heinz Josef ^b   Richel, Dick J ^b   Sparidans, Rolf W ^c   Weterman, Mariette J ^b   Beijnen, Jos H ^c,d   Schellens, Jan H M ^a,c   Wilmink, Johanna W ^b  

^a NETHERLANDS CANCER INSTITUTE   (Netherlands)

^b ACADEMIC MEDICAL CENTER   (Netherlands)

^c UTRECHT UNIVERSITY   (Netherlands)

^d SLOTERVAART HOSPITAL   (Netherlands)

Author keywords

Capecitabine; Clinical pharmacology. Everolimus; mTOR; Pharmacokinetics; Phase I

Indexed keywords

5' DEOXY 5 FLUOROCYTIDINE; ALANINE AMINOTRANSFERASE; ALKALINE PHOSPHATASE; ASPARTATE AMINOTRANSFERASE; BILIRUBIN; CAPECITABINE; DIHYDROFLUOROURACIL; DOXIFLURIDINE; EVEROLIMUS; FLUOROURACIL; GAMMA GLUTAMYLTRANSFERASE;

ADULT; ADVANCED CANCER; AGED; AGEUSIA; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; ANGIONEUROTIC EDEMA; ANOREXIA; AREA UNDER THE CURVE; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CANCER COMBINATION CHEMOTHERAPY; CANCER CONTROL; CANCER PATIENT; CLINICAL ARTICLE; CONSTIPATION; DIARRHEA; DOSE RESPONSE; DRUG ABSORPTION; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG ERUPTION; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; FEASIBILITY STUDY; FEMALE; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; HAND FOOT SYNDROME; HUMAN; HUMAN CELL; HYPERCALCEMIA; HYPERCHOLESTEROLEMIA; HYPERKALEMIA; HYPERTRIGLYCERIDEMIA; HYPOKALEMIA; HYPONATREMIA; LEUKOCYTE; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUROPATHY; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; SIDE EFFECT; SOLID TUMOR; STOMATITIS; THROMBOCYTE; THROMBOCYTOPENIA; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT DURATION;

ADMINISTRATION, ORAL; ADULT; AGED; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; AREA UNDER CURVE; DEOXYCYTIDINE; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; FLUOROURACIL; HUMANS; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; NEOPLASM STAGING; NEOPLASMS; PROTEIN KINASE INHIBITORS; SIROLIMUS; TOR SERINE-THREONINE KINASES; YOUNG ADULT;

EID: 84866730140     PISSN: 01676997     EISSN: 15730646     Source Type: Journal    
DOI: 10.1007/s10637-011-9723-4     Document Type: Article

References (36)

1. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11:32-50
2. Aoki M, Blazek E, Vogt PK. (2001) A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci USA 98:136-141
3. Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O'Reilly T, Natt F, Hall J, Lane HA, Thomas G. (2005) The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120:747-759
4. Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, Tobler S, Heusser C, O'Reilly T, Stolz B, Marti A, Thomas G, Lane HA. (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252-261
5. Boulay A, Rudloff J, Ye J, Zumstein-Mecker S, O'Reilly T, Evans DB, Chen S, Lane HA. (2005) Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 11:5319-5328
6. Seeliger H, Guba M, Kleespies A, Jauch KW, Bruns CJ. (2007) Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev 26:611-621
7. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR. (2004) mTOR inhibition reverses Aktdependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594-601
8. Goudar RK, Shi Q, Hjelmeland MD, Keir ST, McLendon RE, Wikstrand CJ, Reese ED, Conrad CA, Traxler P, Lane HA, Reardon DA, Cavenee WK, Wang XF, Bigner DD, Friedman HS, Rich JN. (2005) Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2. (AEE788) and the mammalian target of rapamycin. (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4:101-112
9. Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, Schilder RJ, Ozols RF, Testa JR. (2007) RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 13:4261-4270
10. Khariwala SS, Kjaergaard J, Lorenz R, Van Lente F, Shu S, Strome M. (2006) Everolimus. (RAD) inhibits in vivo growth of murine squamous cell carcinoma. (SCC VII). Laryngoscope 116:814-820
11. Zitzmann K, De Toni EN, Brand S, Goke B, Meinecke J, Spottl G, Meyer HH, Auernhammer CJ. (2007) The novel mTOR inhibitor RAD001. (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology 85:54-60
12. Matsuzaki T, Yashiro M, Kaizaki R, Yasuda K, Doi Y, Sawada T, Ohira M, Hirakawa K. (2009) Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. Cancer Sci
13. Bu X, Le C, Jia F, Guo X, Zhang L, Zhang B, Wu M, Wei L. (2008) Synergistic effect of mTOR inhibitor rapamycin and fluorouracil in inducing apoptosis and cell senescence in hepatocarcinoma cells. Cancer Biol Ther 7:392-396
14. Seeliger H, Guba M, Koehl GE, Doenecke A, Steinbauer M, Bruns CJ, Wagner C, Frank E, Jauch KW, Geissler EK. (2004) Blockage of 2-deoxy-D-ribose-induced angiogenesis with rapamycin counteracts a thymidine phosphorylase-based escape mechanism available for colon cancer under 5-fluorouracil therapy. Clin Cancer Res 10:1843-1852
15. Lee KH, Hur HS, Im SA, Lee J, Kim HP, Yoon YK, Han SW, Song SH, Oh DY, Kim TY, Bang YJ. (2010) RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregulating thymidylate synthase. Cancer Lett 299:22-28
16. 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. (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449-456
17. Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP. (2009) A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001. (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 115:2438-2446
18. Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, Enzinger PC, Allen B, Clark JW, Ryan DP, Fuchs CS. (2009) Oral mTOR inhibitor everolimus in patients with gemcitabinerefractory metastatic pancreatic cancer. J Clin Oncol 27:193-198
19. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van CE, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K. (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514-523
20. Ellard SL, Clemons M, Gelmon KA, Norris B, Kennecke H, Chia S, Pritchard K, Eisen A, Vandenberg T, Taylor M, Sauerbrei E, Mishaeli M, Huntsman D, WalshW, Olivo M, McIntosh L, Seymour L. (2009) Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 27:4536-4541
21. Soria JC, Shepherd FA, Douillard JY, Wolf J, Giaccone G, Crino L, Cappuzzo F, Sharma S, Gross SH, Dimitrijevic S, Di Scala L, Gardner H, Nogova L, Papadimitrakopoulou V. (2009) Efficacy of everolimus. (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol 20:1674-1681
22. O'Donnell A, Faivre S, Burris HA III, 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 26:1588-1595
23. Okamoto I, Doi T, Ohtsu A, Miyazaki M, Tsuya A, Kurei K, Kobayashi K, Nakagawa K. (2010) Phase I clinical and pharmacokinetic study of RAD001. (everolimus) administered daily to Japanese patients with advanced solid tumors. Jpn J Clin Oncol 40:17-23
24. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, 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 26:1603-1610
25. Campone M, Levy V, Bourbouloux E, Berton Rigaud D, Bootle D, Dutreix C, Zoellner U, Shand N, Calvo F, Raymond E. (2009) Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. Br J Cancer 100:315-321
26. Andre F, Campone M, O'Regan R, Manlius C, Massacesi C, Sahmoud T, Mukhopadhyay P, Soria JC, Naughton M, Hurvitz SA. (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28:5110-5115
27. Pacey S, Rea D, Steven N et al. (2004) Results of a phase 1 clinical trial investigation a combination of the oral mTOR-inhibitor Everolimus. (E, RAD001) andGemcitabine. (GEM) in patients. (pts) with advanced cancers. J Clin Oncol 22(14Supplement):3120, Ref Type: Abstract
28. Milton DT, Riely GJ, Azzoli CG, Gomez JE, Heelan RT, Kris MG, Krug LM, Pao W, Pizzo B, Rizvi NA, Miller VA. (2007) Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 110:599-605
29. Hainsworth JD, Infante JR, Spigel DR, Peyton JD, Thompson DS, Lane CM, Clark BL, Rubin MS, Trent DF, Burris HA III. (2010) Bevacizumab and everolimus in the treatment of patients with metastatic melanoma: a phase 2 trial of the Sarah Cannon Oncology Research Consortium. Cancer 116:4122-4129
30. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS. (2009) Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2630-2637
31. Lim T, Lee J, Lee DJ, Lee HY, Han B, Baek KK, Ahn HK, Lee SJ, Park SH, Park JO, Park YS, Lim HY, Kim KM, Kang WK. (2011) Phase I trial of capecitabine plus everolimus. (RAD001) in patients with previously treated metastatic gastric cancer. Cancer Chemother Pharmacol
32. 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. J Natl Cancer Inst 92:205-216
33. Vainchtein LD, Rosing H, Schellens JH, Beijnen JH. (2009) A new, validated HPLC-MS/MS method for the simultaneous determination of the anti-cancer agent capecitabine and its metabolites: 5'- deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, 5-fluorouracil and 5-fluorodihydrouracil, in human plasma. Biomed Chromatogr
34. Punt CJ, Boni J, Bruntsch U, Peters M, Thielert C. (2003) Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cellcycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 14:931-937
35. Deenen MJ, Boot H, Dubbelman R, Jansen EPM, Beijnen JH, Verheij M, Schellens JHM, Cats A. (2011) The effect of gastric surgery and radiotherapy on the exposure to capecitabine. Br J Clin Pharmacol 70(6):918, Ref Type: Abstract
36. Reigner B, Blesch K, Weidekamm E. (2001) Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 40:85-104