Erlotinib and Temsirolimus for Solid Tumors

Summary

Define the maximum tolerated dose and dose limiting side-effects of temsirolimus in combination wtih erlotinib in patients with resistant solid tumors

Timeline

Start

2009-05

Primary completion

2014-09

Completion

2014-09

Publications

• Background Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005 Apr;16(4):525-37. doi: 10.1093/annonc/mdi113. Epub 2005 Feb 22.
• Background Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995 Jan 13;270(2):815-22. doi: 10.1074/jbc.270.2.815.
• Background Lorenz MC, Heitman J. TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem. 1995 Nov 17;270(46):27531-7. doi: 10.1074/jbc.270.46.27531.
• Background Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett. 2005;10(3):479-98.
• Background O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006 Feb 1;66(3):1500-8. doi: 10.1158/0008-5472.CAN-05-2925.
• Background Oldham S, Hafen E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol. 2003 Feb;13(2):79-85. doi: 10.1016/s0962-8924(02)00042-9.
• Background Bianco R, Melisi D, Ciardiello F, Tortora G. Key cancer cell signal transduction pathways as therapeutic targets. Eur J Cancer. 2006 Feb;42(3):290-4. doi: 10.1016/j.ejca.2005.07.034. Epub 2006 Jan 11.
• Background Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004 Jul 15;22(14):2954-63. doi: 10.1200/JCO.2004.02.141.
• Background DeGraffenried LA, Fulcher L, Friedrichs WE, Grunwald V, Ray RB, Hidalgo M. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann Oncol. 2004 Oct;15(10):1510-6. doi: 10.1093/annonc/mdh388.
• Background Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002 Jul;10(1):151-62. doi: 10.1016/s1097-2765(02)00568-3.
• Background Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene. 2000 Dec 27;19(56):6680-6. doi: 10.1038/sj.onc.1204091.
• Background Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol. 2004 Nov;16(6):564-75. doi: 10.1097/01.cco.0000143964.74936.d1.
• Background Blagosklonny MV, Darzynkiewicz Z. Four birds with one stone: RAPA as potential anticancer therapy. Cancer Biol Ther. 2002 Jul-Aug;1(4):359-61. No abstract available.
• Background Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol. 2003 Feb;4(2):75-85. doi: 10.1016/s1470-2045(03)00979-3.
• Background Dudkin L, Dilling MB, Cheshire PJ, Harwood FC, Hollingshead M, Arbuck SG, Travis R, Sausville EA, Houghton PJ. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res. 2001 Jun;7(6):1758-64.
• Background Yu K, Toral-Barza L, Discafani C, Zhang WG, Skotnicki J, Frost P, Gibbons JJ. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer. 2001 Sep;8(3):249-58. doi: 10.1677/erc.0.0080249.
• Background Geoerger B, Kerr K, Tang CB, Fung KM, Powell B, Sutton LN, Phillips PC, Janss AJ. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res. 2001 Feb 15;61(4):1527-32.
• Background Elit L. CCI-779 Wyeth. Curr Opin Investig Drugs. 2002 Aug;3(8):1249-53.
• Background Teachey DT, Obzut DA, Cooperman J, Fang J, Carroll M, Choi JK, Houghton PJ, Brown VI, Grupp SA. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood. 2006 Feb 1;107(3):1149-55. doi: 10.1182/blood-2005-05-1935. Epub 2005 Sep 29.
• Background Peralba JM, DeGraffenried L, Friedrichs W, Fulcher L, Grunwald V, Weiss G, Hidalgo M. Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients. Clin Cancer Res. 2003 Aug 1;9(8):2887-92.
• Background Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol. 2004 Jun 15;22(12):2336-47. doi: 10.1200/JCO.2004.08.116. Epub 2004 May 10.
• Background Hidalgo, M., Rowinsky, E, Erlichman,C, Drengler, R, Marshall, B, Marks, R, Edwards, T, Boni, J, et al., Phase I and Pharmocologic Study of CCI-779, a Cell Cycle Inhibitor. 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy., 2000.
• Background Raymond, E., Alexandre, J, Depenbrock, H et al., CCI-779, a Rapamycin Analog with Antitumor Activity: A Phase I Study utilizing a Weekly Schedule. Proc Am Soc Clin Oncol, 2000.
• Background Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs. 2002 Feb;3(2):295-304.
• Background Hidalgo, M., Rowinsky, E, Erlichman,C, et al., CCI-779, a Rapamycin Analog and Multifaceted Inhibitor of Signal Transduction: a Phase I Study. Proc Am Soc Clin Oncol, 2000. 19.
• Background Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004 Mar 1;22(5):909-18. doi: 10.1200/JCO.2004.08.185.
• Background Pandya KJ, Dahlberg S, Hidalgo M, Cohen RB, Lee MW, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group (E1500). A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J Thorac Oncol. 2007 Nov;2(11):1036-41. doi: 10.1097/JTO.0b013e318155a439.
• Background Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR, Gross H, Kaufmann SH. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005 Aug 10;23(23):5347-56. doi: 10.1200/JCO.2005.13.466. Epub 2005 Jun 27.
• Background Oza, A., Elit, L, Biagi, J, Gotlieb, W, Tonkin, K, Tsao, MN, et al., A Phase II Study of Temsirolimus (CCI-779) in Patients with Metastatic and/or Recurrent Endometrial Cancer - NCI-CTG IND.160. Clin Cancer Res, 2005. 11(24): p. 9099s.
• Background Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, De Angelis L, Raizer J, Hess K, Aldape K, Lamborn KR, Kuhn J, Dancey J, Prados MD; North American Brain Tumor Consortium and the National Cancer Institute. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005 Aug;23(4):357-61. doi: 10.1007/s10637-005-1444-0.
• Background Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, Doroshow JH. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer. 2005 Sep 1;104(5):1045-8. doi: 10.1002/cncr.21265.
• Background Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM, Jenkins RB, Dakhil SR, Morton RF, Jaeckle KA, Scheithauer BW, Dancey J, Hidalgo M, Walsh DJ; North Central Cancer Treatment Group. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol. 2005 Aug 10;23(23):5294-304. doi: 10.1200/JCO.2005.23.622. Epub 2005 Jul 5.
• Background Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, Eiermann W, Hess D, Morant R, Semiglazov V, Borner M, Salzberg M, Ostapenko V, Illiger HJ, Behringer D, Bardy-Bouxin N, Boni J, Kong S, Cincotta M, Moore L. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol. 2005 Aug 10;23(23):5314-22. doi: 10.1200/JCO.2005.66.130. Epub 2005 Jun 13.
• Background Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. doi: 10.1056/NEJMoa066838.
• Background Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006 Aug;33(4):369-85. doi: 10.1053/j.seminoncol.2006.04.003.
• Background Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232. doi: 10.1016/1040-8428(94)00144-i. No abstract available.
• Background Fox SB, Smith K, Hollyer J, Greenall M, Hastrich D, Harris AL. The epidermal growth factor receptor as a prognostic marker: results of 370 patients and review of 3009 patients. Breast Cancer Res Treat. 1994 Jan;29(1):41-9. doi: 10.1007/BF00666180.
• Background Fry DW. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy: progression from reversible to irreversible inhibitors. Pharmacol Ther. 1999 May-Jun;82(2-3):207-18. doi: 10.1016/s0163-7258(98)00050-3.
• Background Neal DE, Mellon K. Epidermal growth factor receptor and bladder cancer: a review. Urol Int. 1992;48(4):365-71. doi: 10.1159/000282357.
• Background Parra HS, Cavina R, Latteri F, Zucali PA, Campagnoli E, Morenghi E, Grimaldi GC, Roncalli M, Santoro A. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004 Jul 19;91(2):208-12. doi: 10.1038/sj.bjc.6601923.
• Background Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther. 1999 May-Jun;82(2-3):241-50. doi: 10.1016/s0163-7258(98)00045-x.
• Background Wosikowski K, Schuurhuis D, Johnson K, Paull KD, Myers TG, Weinstein JN, Bates SE. Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns. J Natl Cancer Inst. 1997 Oct 15;89(20):1505-15. doi: 10.1093/jnci/89.20.1505.
• Background Meyers MB, Shen WP, Spengler BA, Ciccarone V, O'Brien JP, Donner DB, Furth ME, Biedler JL. Increased epidermal growth factor receptor in multidrug-resistant human neuroblastoma cells. J Cell Biochem. 1988 Oct;38(2):87-97. doi: 10.1002/jcb.240380203.
• Background Giralt J, Eraso A, Armengol M, Rossello J, Majo J, Ares C, Espin E, Benavente S, de Torres I. Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1460-5. doi: 10.1016/s0360-3016(02)03752-5.
• Background Brabender J, Danenberg KD, Metzger R, Schneider PM, Park J, Salonga D, Holscher AH, Danenberg PV. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res. 2001 Jul;7(7):1850-5.
• Background Saif MW. Erlotinib: the first biologic in the management of pancreatic cancer. Expert Opin Pharmacother. 2008 Jun;9(9):1595-607. doi: 10.1517/14656566.9.9.1595.
• Background Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, Eckhardt SG, Tolcher A, Britten CD, Denis L, Ferrante K, Von Hoff DD, Silberman S, Rowinsky EK. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001 Jul 1;19(13):3267-79. doi: 10.1200/JCO.2001.19.13.3267.
• Background Perez-Soler R. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin Cancer Res. 2004 Jun 15;10(12 Pt 2):4238s-4240s. doi: 10.1158/1078-0432.CCR-040017.
• Background Miller VA, Hirsch FR, Johnson DH. Systemic therapy of advanced bronchioloalveolar cell carcinoma: challenges and opportunities. J Clin Oncol. 2005 May 10;23(14):3288-93. doi: 10.1200/JCO.2005.19.240.
• Background Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004 Jan 1;22(1):77-85. doi: 10.1200/JCO.2004.06.075.
• Background Gordon AN, Finkler N, Edwards RP, Garcia AA, Crozier M, Irwin DH, Barrett E. Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. Int J Gynecol Cancer. 2005 Sep-Oct;15(5):785-92. doi: 10.1111/j.1525-1438.2005.00137.x.
• Background Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M, Kapadia A, Rabbitt J, Page MS, Fedoroff A, Xie D, Kelley SK. Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol. 2006 Jan;8(1):67-78. doi: 10.1215/S1522851705000451.
• Background Raizer JJ. HER1/EGFR tyrosine kinase inhibitors for the treatment of glioblastoma multiforme. J Neurooncol. 2005 Aug;74(1):77-86. doi: 10.1007/s11060-005-0603-7.
• Background Dragovich T, McCoy S, Fenoglio-Preiser CM, Wang J, Benedetti JK, Baker AF, Hackett CB, Urba SG, Zaner KS, Blanke CD, Abbruzzese JL. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006 Oct 20;24(30):4922-7. doi: 10.1200/JCO.2006.07.1316.
• Background Mancuso A, Sternberg CN. New treatments for metastatic kidney cancer. Can J Urol. 2005 Feb;12 Suppl 1:66-70; discussion 105.
• Background Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. doi: 10.1056/NEJMoa050753.
• Background Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. doi: 10.1200/JCO.2005.02.840. Epub 2005 Jul 25.
• Background Gatzemeier U. Targeting the HER1/EGFR receptor to improve outcomes in non-small-cell lung cancer. Oncology (Williston Park). 2003 Nov;17(11 Suppl 12):7-10.
• Background Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006 Aug;5(8):671-88. doi: 10.1038/nrd2062.
• Background Buck E, Eyzaguirre A, Brown E, Petti F, McCormack S, Haley JD, Iwata KK, Gibson NW, Griffin G. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther. 2006 Nov;5(11):2676-84. doi: 10.1158/1535-7163.MCT-06-0166.
• Background Boffa DJ, Luan F, Thomas D, Yang H, Sharma VK, Lagman M, Suthanthiran M. Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):293-300. doi: 10.1158/1078-0432.ccr-0629-3.
• Background Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005 Aug 15;65(16):7052-8. doi: 10.1158/0008-5472.CAN-05-0917.
• Background Jimeno A, Kulesza P, Wheelhouse J, Chan A, Zhang X, Kincaid E, Chen R, Clark DP, Forastiere A, Hidalgo M. Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy. Br J Cancer. 2007 Mar 26;96(6):952-9. doi: 10.1038/sj.bjc.6603656. Epub 2007 Mar 6.
• Background Robins, H.I., Wen, P.Y, Chang, S.M, Kuhn, K, et al., Phase I study of erlotinib and CCI-779 (temsirolimus) for patients, with recurrent malignant gliomas (MG) (NABTC 04-02). J Clin Oncol, 2007. 25(18s): p. 2057.
• Background Azzariti A, Porcelli L, Gatti G, Nicolin A, Paradiso A. Synergic antiproliferative and antiangiogenic effects of EGFR and mTor inhibitors on pancreatic cancer cells. Biochem Pharmacol. 2008 Mar 1;75(5):1035-44. doi: 10.1016/j.bcp.2007.11.018. Epub 2007 Dec 3.
• Background 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. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010 Aug;120(8):2858-66. doi: 10.1172/JCI37539. Epub 2010 Jul 26.
• Background Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.
• Park H, Williams K, Trikalinos NA, Larson S, Tan B, Waqar S, Suresh R, Morgensztern D, Van Tine BA, Govindan R, Luo J, Lockhart AC, Wang-Gillam A. A phase I trial of temsirolimus and erlotinib in patients with refractory solid tumors. Cancer Chemother Pharmacol. 2021 Mar;87(3):337-347. doi: 10.1007/s00280-020-04183-0. Epub 2020 Nov 6.

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Indications