Advertisement

Journal of Neuro-Oncology

, Volume 96, Issue 2, pp 219–230 | Cite as

Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma

  • David A. ReardonEmail author
  • Annick Desjardins
  • James J. Vredenburgh
  • Sridharan Gururangan
  • Allan H. Friedman
  • James E. HerndonII
  • Jennifer Marcello
  • Julie A. Norfleet
  • Roger E. McLendon
  • John H. Sampson
  • Henry S. Friedman
Clinical Study - Patient Study

Abstract

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade ≥2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).

Keywords

Malignant glioma EGFR mTOR Erlotinib Sirolimus 

Abbreviations list

ANC

Absolute neutrophil count

AST

Aspartate aminotransferase

BBB

Blood-brain barrier

BUN

Blood urea nitrogen

CBC

Complete blood count

CI

Confidence intervals

CNS

Central nervous system

CR

Complete response

CTC

Common Toxicity Criteria

CYP

Cytochrome p450

DLT

Dose-limiting toxicity

EGFR

Epidermal growth factor receptor

EIAEDs

Enzyme-inducing antieptileptic drugs

EGFR

Epidermal growth factor receptor

GBM

Glioblastoma multiforme

GS

Gliosarcoma

IRB

Institutional review board

ITT

Intent-to treat

KPS

Karnofsky performance status

MG

Malignant glioma

MTD

Maximum-tolerated dose

mTOR

Mammalian target of rapamycin

NCI

National Cancer Institute

NE

Non-estimable

pAKT

Phosphorylated akt murine thymomoa viral oncogene homologue 1

PD

Progressive disease

PFS

Progression-free survival

P-gp

p-glycoprotein

pMAPK

Phosphorylated mitogen activated protein kinase

PR

Partial response

pS-6

Phosphorylated S-6 ribosomal protein

PTEN

Phosphatase and tensin homologue

SD

Stable disease

TKI

Tyrosine kinase inhibitor

VEGF

Vascular endothelial growth factor

XRT

External beam radiotherapy

Notes

Acknowledgement

This work was supported by NIH Grants NS20023 and CA11898; NIH Grant MO1 RR 30, GCRC Program, NCRR; and NCI SPORE 1 P20 CA096890

References

  1. 1.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  2. 2.
    Vredenburgh JJ, Desjardins A, Herndon JE II, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729CrossRefPubMedGoogle Scholar
  3. 3.
    Cloughesy TF, Prados MD, Mikkelsen T, Abrey LE, Schiff D, Yung WK, Maoxia Z, Dimery I, Friedman HS (2008) A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). In: Grunberg SM (ed) Proceedings of the American Society for Clinical Oncology, Chicago, IL, p 91Google Scholar
  4. 4.
    Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745CrossRefPubMedGoogle Scholar
  5. 5.
    Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  6. 6.
    Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, Deangelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-oncology 10:162–170CrossRefPubMedGoogle Scholar
  7. 7.
    Ballman KV, Buckner JC, Brown PD, Giannini C, Flynn PJ, LaPlant BR, Jaeckle KA (2007) The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro-oncology 9:29–38CrossRefPubMedGoogle Scholar
  8. 8.
    Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A, Inge L, Smith BL, Sawyers CL, Mischel PS (2003) Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 63:2742–2746PubMedGoogle Scholar
  9. 9.
    Ruano Y, Mollejo M, Camacho FI, Rodriguez de Lope A, Fiano C, Ribalta T, Martinez P, Hernandez-Moneo JL, Melendez B (2008) Identification of survival-related genes of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma multiforme. Cancer 112:1575–1584CrossRefPubMedGoogle Scholar
  10. 10.
    Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501CrossRefPubMedGoogle Scholar
  11. 11.
    Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A, Loeffler JS (2004) The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 22:1926–1933CrossRefPubMedGoogle Scholar
  12. 12.
    Schmelzle T, Hall MN (2000) TOR, a central controller of cell growth. Cell 103:253–262CrossRefPubMedGoogle Scholar
  13. 13.
    Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha Santos G, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA (2005) Erlotinib in lung cancer––molecular and clinical predictors of outcome. N Engl J Med 353:133–144CrossRefPubMedGoogle Scholar
  14. 14.
    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 (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132CrossRefPubMedGoogle Scholar
  15. 15.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966CrossRefPubMedGoogle Scholar
  16. 16.
    Seufferlein T, Rozengurt E (1996) Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res 56:3895–3897PubMedGoogle Scholar
  17. 17.
    Hosoi H, Dilling MB, Shikata T, Liu LN, Shu L, Ashmun RA, Germain GS, Abraham RT, Houghton PJ (1999) Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res 59:886–894PubMedGoogle Scholar
  18. 18.
    Hosoi H, Dilling MB, Liu LN, Danks MK, Shikata T, Sekulic A, Abraham RT, Lawrence JC Jr, Houghton PJ (1998) Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol Pharmacol 54:815–824PubMedGoogle Scholar
  19. 19.
    Grewe M, Gansauge F, Schmid RM, Adler G, Seufferlein T (1999) Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res 59:3581–3587PubMedGoogle Scholar
  20. 20.
    Majewski M, Korecka M, Kossev P, Li S, Goldman J, Moore J, Silberstein LE, Nowell PC, Schuler W, Shaw LM, Wasik MA (2000) The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: a potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. Proc Natl Acad Sci U S A 97:4285–4290CrossRefPubMedGoogle Scholar
  21. 21.
    Dudkin L, Dilling MB, Cheshire PJ, Harwood FC, Hollingshead M, Arbuck SG, Travis R, Sausville EA, Houghton PJ (2001) Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7:1758–1764PubMedGoogle Scholar
  22. 22.
    Jiang W, Cazacu S, Xiang C, Zenklusen JC, Fine HA, Berens M, Armstrong B, Brodie C, Mikkelsen T (2008) FK506 binding protein mediates glioma cell growth and sensitivity to rapamycin treatment by regulating NF-kappaB signaling pathway. Neoplasia 10:235–243PubMedGoogle Scholar
  23. 23.
    Geoerger B, Kerr K, Tang CB, Fung KM, Powell B, Sutton LN, Phillips PC, Janss AJ (2001) Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 61:1527–1532PubMedGoogle Scholar
  24. 24.
    Eshleman JS, Carlson BL, Mladek AC, Kastner BD, Shide KL, Sarkaria JN (2002) Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62:7291–7297PubMedGoogle Scholar
  25. 25.
    Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE 2nd, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142CrossRefPubMedGoogle Scholar
  26. 26.
    Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M, Kapadia A, Rabbitt J, Page MS, Fedoroff A, Xie D, Kelley SK (2006) Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro-oncol 8:67–78CrossRefPubMedGoogle Scholar
  27. 27.
    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 (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group study. J Clin Oncol 23:5294–5304CrossRefPubMedGoogle Scholar
  28. 28.
    Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL (2008) Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS medicine 5:e8CrossRefPubMedGoogle Scholar
  29. 29.
    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 (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357–361CrossRefPubMedGoogle Scholar
  30. 30.
    Chang SM, Kuhn J, Wen P, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, Cloughesy T, De Angelis L, Razier J, Hess K, Dancey J, Prados MD (2004) Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs 22:427–435CrossRefPubMedGoogle Scholar
  31. 31.
    Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R (2008) Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res 14:957–960CrossRefPubMedGoogle Scholar
  32. 32.
    van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF, Armand JP, Taphoorn MJ, Tosoni A, Kletzl H, Klughammer B, Lacombe D, Gorlia T (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27:1268–1274CrossRefPubMedGoogle Scholar
  33. 33.
    Rao RD, Mladek AC, Lamont JD, Goble JM, Erlichman C, James CD, Sarkaria JN (2005) Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. Neoplasia 7:921–929CrossRefPubMedGoogle Scholar
  34. 34.
    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 4:101–112PubMedGoogle Scholar
  35. 35.
    Li J, Zhao M, He P, Hidalgo M, Baker SD (2007) Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res 13:3731–3737CrossRefPubMedGoogle Scholar
  36. 36.
    Kuhn JG, Chang SM, Wen PY, Cloughesy TF, Greenberg H, Schiff D, Conrad C, Fink KL, Robins HI, Mehta M, DeAngelis L, Raizer J, Hess K, Lamborn KR, Dancey J, Prados MD (2007) Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma. Clin Cancer Res 13:7401–7406CrossRefPubMedGoogle Scholar
  37. 37.
    Reardon DA, Quinn JA, Vredenburgh JJ, Gururangan S, Friedman AH, Desjardins A, Sathornsumetee S, Herndon JE 2nd, Dowell JM, McLendon RE, Provenzale JM, Sampson JH, Smith RP, Swaisland AJ, Ochs JS, Lyons P, Tourt-Uhlig S, Bigner DD, Friedman HS, Rich JN (2006) Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 12:860–868CrossRefPubMedGoogle Scholar
  38. 38.
    Reardon DA, Quinn JA, Vredenburgh J, Rich JN, Gururangan S, Badruddoja M, Herndon JE 2nd, Dowell JM, Friedman AH, Friedman HS (2005) Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma. Cancer 103:329–338CrossRefPubMedGoogle Scholar
  39. 39.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  40. 40.
    Pelloski CE, Lin E, Zhang L, Yung WK, Colman H, Liu JL, Woo SY, Heimberger AB, Suki D, Prados M, Chang S, Barker FG 3rd, Fuller GN, Aldape KD (2006) Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res 12:3935–3941CrossRefPubMedGoogle Scholar
  41. 41.
    Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B, Abrey LE, Raizer J, Cloughesy TF, Fink K, Gilbert M, Chang S, Junck L, Schiff D, Lieberman F, Fine HA, Mehta M, Robins HI, DeAngelis LM, Groves MD, Puduvalli VK, Levin V, Conrad C, Maher EA, Aldape K, Hayes M, Letvak L, Egorin MJ, Capdeville R, Kaplan R, Murgo AJ, Stiles C, Prados MD (2006) Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium study 99–08. Clin Cancer Res 12:4899–4907CrossRefPubMedGoogle Scholar
  42. 42.
    Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR, Prados MD (2006) Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium study. J Clin Oncol 24:3651–3656CrossRefPubMedGoogle Scholar
  43. 43.
    Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert B, Clement PM, Frenay M, Rampling R, Stupp R, Kros JM, Heinrich MC, Gorlia T, Lacombe D, van den Bent MJ (2008) Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group study. J Clin Oncol 26:4659–4665CrossRefPubMedGoogle Scholar
  44. 44.
    Li B, Chang CM, Yuan M, McKenna WG, Shu HK (2003) Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. Cancer Res 63:7443–7450PubMedGoogle Scholar
  45. 45.
    She QB, Solit D, Basso A, Moasser MM (2003) Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin Cancer Res 9:4340–4346PubMedGoogle Scholar
  46. 46.
    Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA (2006) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9:341–349CrossRefPubMedGoogle Scholar
  47. 47.
    Wang MY, Lu KV, Zhu S, Dia EQ, Vivanco I, Shackleford GM, Cavenee WK, Mellinghoff IK, Cloughesy TF, Sawyers CL, Mischel PS (2006) Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res 66:7864–7869CrossRefPubMedGoogle Scholar
  48. 48.
    Doherty L, Gigas DC, Kesari S, Drappatz J, Kim R, Zimmerman J, Ostrowsky L, Wen PY (2006) Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 67:156–158CrossRefPubMedGoogle Scholar
  49. 49.
    Kreisl TN, Lassman AB, Mischel PS, Rosen N, Scher HI, Teruya-Feldstein J, Shaffer D, Lis E, Abrey LE (2009) A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol 92:99–105CrossRefPubMedGoogle Scholar
  50. 50.
    Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J Clin Oncol 22:785–794CrossRefPubMedGoogle Scholar
  51. 51.
    Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial––INTACT 1. J Clin Oncol 22:777–784CrossRefPubMedGoogle Scholar
  52. 52.
    Lassman AB, Rossi MR, Razier JR, Abrey LE, Lieberman FS, Grefe CN, Lamborn K, Pao W, Shih AH, Kuhn JG, Wilson R, Nowak NJ, Cowell JK, DeAngelis LM, Wen P, Gilbert MR, Chang S, Yung WA, Prados M, Holland EC (2005) Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from north american brain tumor consortium trials 01–03 and 00–01. Clin Cancer Res 11:7841–7850CrossRefPubMedGoogle Scholar
  53. 53.
    Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65:7052–7058CrossRefPubMedGoogle Scholar
  54. 54.
    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 (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508CrossRefPubMedGoogle Scholar
  55. 55.
    Ozvegy-Laczka C, Cserepes J, Elkind NB, Sarkadi B (2005) Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters. Drug Resist Updat 8:15–26CrossRefPubMedGoogle Scholar
  56. 56.
    Marchetti S, de Vries NA, Buckle T, Bolijn MJ, van Eijndhoven MA, Beijnen JH, Mazzanti R, van Tellingen O, Schellens JH (2008) Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther 7:2280–2287CrossRefPubMedGoogle Scholar
  57. 57.
    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024CrossRefPubMedGoogle Scholar
  58. 58.
    Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, Baumber R, Lamborn KR, Kapadia A, Malec M, Berger MS, Stokoe D (2005) Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 97:880–887PubMedCrossRefGoogle Scholar
  59. 59.
    Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, Ayers-Ringler J, Rabbitt J, Page M, Fedoroff A, Sneed PK, Berger MS, McDermott MW, Parsa AT, Vandenberg S, James CD, Lamborn KR, Stokoe D, Haas-Kogan DA (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 27:579–584CrossRefPubMedGoogle Scholar
  60. 60.
    de Groot JF, Gilbert MR, Aldape K, Hess KR, Hanna TA, Ictech S, Groves MD, Conrad C, Colman H, Puduvalli VK, Levin V, Yung WK (2008) Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma. J Neurooncol 90:89–97CrossRefPubMedGoogle Scholar
  61. 61.
    Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH, Geoffroy FJ, Arusell R, Kitange G, Jenkins RB, Kugler JW, Morton RF, Rowland KM Jr, Mischel P, Yong WH, Scheithauer BW, Schiff D, Giannini C, Buckner JC (2008) Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group study N0177. J Clin Oncol 26:5603–5609CrossRefPubMedGoogle Scholar
  62. 62.
    Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98:10314–10319CrossRefPubMedGoogle Scholar
  63. 63.
    Yang L, Clarke MJ, Carlson BL, Mladek AC, Schroeder MA, Decker P, Wu W, Kitange GJ, Grogan PT, Goble JM, Uhm J, Galanis E, Giannini C, Lane HA, James CD, Sarkaria JN (2008) PTEN loss does not predict for response to RAD001 (Everolimus) in a glioblastoma orthotopic xenograft test panel. Clin Cancer Res 14:3993–4001CrossRefPubMedGoogle Scholar
  64. 64.
    Krishnan S, Brown PD, Ballman KV, Fiveash JB, Uhm JH, Giannini C, Jaeckle KA, Geoffroy FJ, Nabors LB, Buckner JC (2006) Phase I trial of erlotinib with radiation therapy in patients with glioblastoma multiforme: results of North Central Cancer Treatment Group protocol N0177. Int J Radiat Oncol Biol Phys 65:1192–1199PubMedGoogle Scholar
  65. 65.
    Wen P, Kuhn J, Chang S, Lamborn K, Robbins H, Cloughesy T, Lieberman F, Mehta M, Gilbert M, Cooper J, Drappatz J, Kesari S, Norden AD, Groves M, Aldape K, Yung WKA, Dancey J, Prodos M (2008) Phase I/II study of erlotinib and temsirolimus (CCI-779) for patients with recurrent malignant gliomas (NABTC 04-02). In: Yung WKA (ed) 13th Annual Meeting of the Society for Neuro-Oncology, Las Vegas, NV, p 824Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • David A. Reardon
    • 1
    • 2
    • 6
    Email author
  • Annick Desjardins
    • 4
  • James J. Vredenburgh
    • 4
  • Sridharan Gururangan
    • 1
    • 2
  • Allan H. Friedman
    • 1
  • James E. HerndonII
    • 5
  • Jennifer Marcello
    • 5
  • Julie A. Norfleet
    • 1
  • Roger E. McLendon
    • 3
  • John H. Sampson
    • 1
  • Henry S. Friedman
    • 1
    • 2
  1. 1.Department of SurgeryDuke University Medical CenterDurhamUSA
  2. 2.Department of PediatricsDuke University Medical CenterDurhamUSA
  3. 3.Department of PathologyDuke University Medical CenterDurhamUSA
  4. 4.Department of MedicineDuke University Medical CenterDurhamUSA
  5. 5.Cancer Center BiostatisticsDuke University Medical CenterDurhamUSA
  6. 6.The Preston Robert Tisch Brain Tumor Center at DukeDuke University Medical CenterDurhamUSA

Personalised recommendations