Journal of Neuro-Oncology

, Volume 101, Issue 1, pp 57–66 | Cite as

Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma

  • David A. ReardonEmail author
  • James J. Vredenburgh
  • Annick Desjardins
  • Katherine Peters
  • Sridharan Gururangan
  • John H. Sampson
  • Jennifer Marcello
  • James E. HerndonII
  • Roger E. McLendon
  • Dorothea Janney
  • Allan H. Friedman
  • Darell D. Bigner
  • Henry S. Friedman
Clinical Study – Patient Study


Sorafenib, an oral VEGFR-2, Raf, PDGFR, c-KIT and Flt-3 inhibitor, is active against renal cell and hepatocellular carcinomas, and has recently demonstrated promising activity for lung and breast cancers. In addition, various protracted temozolomide dosing schedules have been evaluated as a strategy to further enhance its anti-tumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase 2 trial among recurrent glioblastoma patients. Adult glioblastoma patients at any recurrence after standard temozolomide chemoradiotherapy received sorafenib (400 mg twice daily) and continuous daily temozolomide (50 mg/m2/day). Assessments were performed every eight weeks. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary end points were radiographic response, overall survival (OS), safety and sorafenib pharmacokinetics. Of 32 enrolled patients, 12 (38%) were on CYP3-A inducing anti-epileptics (EIAEDs), 17 (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-planter erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic exposures were comparable on day 1 regardless of EIAED status, but significantly lower on day 28 for patients on EIAEDs (P = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. In conclusion, sorafenib can be safely administered with daily temozolomide, but this regimen has limited activity for recurrent GBM. Co-administration of EIAEDs can lower sorafenib exposures in this population.


Sorafenib Temozolomide Glioblastoma Raf VEGF 



Complete response


Enzyme-inducing antieptileptic drugs


Glioblastoma multiforme


Intent-to treat


Karnofsky performance status


Mitogen-activated protein kinase


Overall survival


Progressive disease


Progression-free survival


Partial response


Stable disease


Vascular endothelial growth factor


Vascular endothelial growth factor receptor



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


  1. 1.
    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
  2. 2.
    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
  3. 3.
    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
  4. 4.
    Vredenburgh JJ, Desjardins A, Herndon JE II, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259CrossRefPubMedGoogle Scholar
  5. 5.
    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
  6. 6.
    Desjardins A, Reardon DA, Herndon JE II, Marcello J, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Bailey L, Bigner DD, Friedman AH, Friedman HS, Vredenburgh JJ (2008) Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. Clin Cancer Res 14:7068–7073CrossRefPubMedGoogle Scholar
  7. 7.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740CrossRefPubMedGoogle Scholar
  8. 8.
    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
  9. 9.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a Pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95CrossRefPubMedGoogle Scholar
  10. 10.
    Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835–844CrossRefPubMedGoogle Scholar
  11. 11.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134CrossRefPubMedGoogle Scholar
  12. 12.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMedGoogle Scholar
  13. 13.
    Denny BJ, Wheelhouse RT, Stevens MF, Tsang LL, Slack JA (1994) NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry 33:9045–9051CrossRefPubMedGoogle Scholar
  14. 14.
    Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C (1997) Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23:35–61CrossRefPubMedGoogle Scholar
  15. 15.
    Brock CS, Newlands ES, Wedge SR, Bower M, Evans H, Colquhoun I, Roddie M, Glaser M, Brampton MH, Rustin GJ (1998) Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 58:4363–4367PubMedGoogle Scholar
  16. 16.
    Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten M, Blaschke B, Meyermann R, Reifenberger G, Weller M, Wick W (2007) Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 25:3357–3361CrossRefPubMedGoogle Scholar
  17. 17.
    Perry JR, Rizek P, Cashman R, Morrison M, Morrison T (2008) Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the “rescue” approach. Cancer 113:2152–2157CrossRefPubMedGoogle Scholar
  18. 18.
    Neyns B, Chaskis C, Joosens E, Menten J, D’Hondt L, Branle F, Sadones J, Michotte A (2008) A multicenter cohort study of dose-dense temozolomide (21 of 28 days) for the treatment of recurrent anaplastic astrocytoma or oligoastrocytoma. Cancer Invest 26:269–277CrossRefPubMedGoogle Scholar
  19. 19.
    Brandes AA, Tosoni A, Cavallo G, Bertorelle R, Gioia V, Franceschi E, Biscuola M, Blatt V, Crino L, Ermani M (2006) Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO). Br J Cancer 95:1155–1160CrossRefPubMedGoogle Scholar
  20. 20.
    Balmaceda C, Peereboom D, Pannullo S, Cheung YK, Fisher PG, Alavi J, Sisti M, Chen J, Fine RL (2008) Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas. Cancer 112:1139–1146CrossRefPubMedGoogle Scholar
  21. 21.
    Wick W, Platten M, Weller M (2009) New (alternative) temozolomide regimens for the treatment of glioma. Neuro-oncology 11:69–79CrossRefPubMedGoogle Scholar
  22. 22.
    Spence AM, Peterson RA, Scharnhorst JD, Silbergeld DL, Rostomily RC (2004) Phase II study of concurrent continuous Temozolomide (TMZ) and Tamoxifen (TMX) for recurrent malignant astrocytic gliomas. J Neurooncol 70:91–95CrossRefPubMedGoogle Scholar
  23. 23.
    Khan RB, Raizer JJ, Malkin MG, Bazylewicz KA, Abrey LE (2002) A phase II study of extended low-dose temozolomide in recurrent malignant gliomas. Neuro-oncology 4:39–43PubMedGoogle Scholar
  24. 24.
    Kong DS, Lee JI, Kim WS, Son MJ, Lim do H, Kim ST, Park K, Kim JH, Eoh W, Nam DH (2006) A pilot study of metronomic temozolomide treatment in patients with recurrent temozolomide-refractory glioblastoma. Oncol Rep 16:1117–1121PubMedGoogle Scholar
  25. 25.
    Berrocal A, Perez Segura P, Gil M, Balana C, Garcia Lopez J, Yaya R, Rodriguez J, Reynes G, Gallego O, Iglesias L (2010) Extended-schedule dose-dense temozolomide in refractory gliomas. J Neurooncol 96(3):417–422CrossRefPubMedGoogle Scholar
  26. 26.
    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
  27. 27.
    Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O’Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA (1999) Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol 17:2762–2771PubMedGoogle Scholar
  28. 28.
    Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (2008) Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 7:3129–3140CrossRefPubMedGoogle Scholar
  29. 29.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954CrossRefPubMedGoogle Scholar
  30. 30.
    Pelloski CE, Lin E, Zhang L, Yung WK, Colman H, Liu JL, Woo SY, Heimberger AB, Suki D, Prados M, Chang S, Barker FG III, 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
  31. 31.
    Martinho O, Longatto-Filho A, Lambros MB, Martins A, Pinheiro C, Silva A, Pardal F, Amorim J, Mackay A, Milanezi F, Tamber N, Fenwick K, Ashworth A, Reis-Filho JS, Lopes JM, Reis RM (2009) Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas. Br J Cancer 101:973–982CrossRefPubMedGoogle Scholar
  32. 32.
    Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52:3213–3219PubMedGoogle Scholar
  33. 33.
    Shih AH, Dai C, Hu X, Rosenblum MK, Koutcher JA, Holland EC (2004) Dose-dependent effects of platelet-derived growth factor-B on glial tumorigenesis. Cancer Res 64:4783–4789CrossRefPubMedGoogle Scholar
  34. 34.
    Joensuu H, Puputti M, Sihto H, Tynninen O, Nupponen NN (2005) Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. J Pathol 207:224–231CrossRefPubMedGoogle Scholar
  35. 35.
    Puputti M, Tynninen O, Sihto H, Blom T, Maenpaa H, Isola J, Paetau A, Joensuu H, Nupponen NN (2006) Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res 4:927–934CrossRefPubMedGoogle Scholar
  36. 36.
    Nabors LB, Rosenfeld MG, Chamberlain SC, Phuphanich S, Batchelor T, Supko JG, Desideri S, Xiaobu Y, Wright J, Grossman S (2007) A Phase I trial of sorafenib (BAY 743-9006) for patients with recurrent or progressive malignant glioma (NABTT 0401). 2007 ASCO Annual Meeting Proceedings, Chicago, IL, p 89 sGoogle Scholar
  37. 37.
    Prados M, Gilbert M, Kuhn K, Lamborn K, Cloughesy T, Lieberman F, Puduvalli VK, Robins HI, Lassman A, Wen PY (2009) Phase I/II study of sorefenib and erlotinib for patients with recurrent glioblastoma (GBM)(NABTC 05-02). American Society of Clinical Oncology, Orlando, FL, p 88 sGoogle Scholar
  38. 38.
    Wen PY, Cloughesy T, Kuhn J, Lamborn K, Abrey LE, Lieberman F, Robins HI, Wright J, Prados MD, Gilbert M (2009) Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM)(NABTC 05-02). American Society of Clinical Oncology, Orlando, FL, p 88 sGoogle Scholar
  39. 39.
    Tolcher AW, Gerson SL, Denis L, Geyer C, Hammond LA, Patnaik A, Goetz AD, Schwartz G, Edwards T, Reyderman L, Statkevich P, Cutler DL, Rowinsky EK (2003) Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004–1011CrossRefPubMedGoogle Scholar
  40. 40.
    Tosoni A, Cavallo G, Ermani M, Scopece L, Franceschi E, Ghimenton C, Gardiman M, Pasetto L, Blatt V, Brandes AA (2006) Is protracted low-dose temozolomide feasible in glioma patients? Neurology 66:427–429CrossRefPubMedGoogle Scholar
  41. 41.
    Perry JR, Belanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot J-F (2010) A phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma. RESCUE study. J Clin Oncol 28(12):2051–2057CrossRefPubMedGoogle Scholar
  42. 42.
    Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T, Lathia C, Petrenciuc O, Moore MJ (2006) Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 12:144–151CrossRefPubMedGoogle Scholar
  43. 43.
    Flaherty KT, Brose M, Schuchter L et al (2004) Phase I/II trial of BAY 43-9006, carboplatin and paclitaxel demonstrated preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma. J Clin Oncol, p 711 sGoogle Scholar
  44. 44.
    Richly H, Kupsch P, Passage K, Grubert M, Hilger RA, Voigtmann R, Schwartz B, Brendel E, Christensen O, Haase CG, Strumberg D (2004) Results of a phase I trial of BAY 43-9006 in combination with doxorubicin in patients with primary hepatic cancer. Int J Clin Pharmacol Ther 42:650–651PubMedGoogle Scholar
  45. 45.
    Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA, Scheulen ME, Christensen O, Brendel E, Schwartz B, Hofstra E, Voigtmann R, Seeber S, Strumberg D (2005) Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer 5:188–196CrossRefPubMedGoogle Scholar
  46. 46.
    Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O’Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U (2009) Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 27:2823–2830CrossRefPubMedGoogle Scholar
  47. 47.
    Jilaveanu L, Zito C, Lee SJ, Nathanson KL, Camp RL, Rimm DL, Flaherty KT, Kluger HM (2009) Expression of sorafenib targets in melanoma patients treated with carboplatin, paclitaxel and sorafenib. Clin Cancer Res 15:1076–1085CrossRefPubMedGoogle Scholar
  48. 48.
    Amaravadi RK, Schuchter LM, McDermott DF, Kramer A, Giles L, Gramlich K, Carberry M, Troxel AB, Letrero R, Nathanson KL, Atkins MB, O’Dwyer PJ, Flaherty KT (2009) Phase II trial of temozolomide and sorafenib in advanced melanoma patients with or without brain metastases. Clin Cancer Res 15:7711–7718CrossRefPubMedGoogle Scholar
  49. 49.
    Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:779–787CrossRefPubMedGoogle Scholar
  50. 50.
    Quant EC, Norden AD, Drappatz J, Muzikansky A, Doherty L, Lafrankie D, Ciampa A, Kesari S, Wen PY (2009) Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro-oncology 11:550–555CrossRefPubMedGoogle Scholar
  51. 51.
    Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ (2005) Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11:5472–5480CrossRefPubMedGoogle Scholar
  52. 52.
    Awada A, Hendlisz A, Gil T, Bartholomeus S, Mano M, de Valeriola D, Strumberg D, Brendel E, Haase CG, Schwartz B, Piccart M (2005) Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 92:1855–1861CrossRefPubMedGoogle Scholar
  53. 53.
    Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P (2006) Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 57:685–692CrossRefPubMedGoogle Scholar
  54. 54.
    Keating GM, Santoro A (2009) Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs 69:223–240CrossRefPubMedGoogle Scholar
  55. 55.
    Moore M, Hirte HW, Siu L, Oza A, Hotte SJ, Petrenciuc O, Cihon F, Lathia C, Schwartz B (2005) Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 16:1688–1694CrossRefPubMedGoogle Scholar
  56. 56.
    Gilbert MR, Supko JG, Batchelor T, Lesser G, Fisher JD, Piantadosi S, Grossman S (2003) Phase I clinical and pharmacokinetic study of irinotecan in adults with recurrent malignant glioma. Clin Cancer Res 9:2940–2949PubMedGoogle Scholar
  57. 57.
    Prados MD, Yung WK, Jaeckle KA, Robins HI, Mehta MP, Fine HA, Wen PY, Cloughesy TF, Chang SM, Nicholas MK, Schiff D, Greenberg HS, Junck L, Fink KL, Hess KR, Kuhn J (2004) Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neuro-oncology 6:44–54CrossRefPubMedGoogle Scholar
  58. 58.
    Santisteban M, Buckner JC, Reid JM, Wu W, Scheithauer BW, Ames MM, Felten SJ, Nikcevich DA, Wiesenfeld M, Jaeckle KA, Galanis E, North Central Cancer Treatment Group (2009) Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results. J Neurooncol 92(2):165–175CrossRefPubMedGoogle Scholar
  59. 59.
    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
  60. 60.
    Reardon DA, Egorin MJ, Quinn JA, Rich JN Sr, Gururangan I, Vredenburgh JJ, Desjardins A, Sathornsumetee S, Provenzale JM, Herndon JE II, Dowell JM, Badruddoja MA, McLendon RE, Lagattuta TF, Kicielinski KP, Dresemann G, Sampson JH, Friedman AH, Salvado AJ, Friedman HS (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368CrossRefPubMedGoogle Scholar
  61. 61.
    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
  62. 62.
    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-oncology 8:67–78CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • David A. Reardon
    • 1
    • 3
    • 7
    Email author
  • James J. Vredenburgh
    • 4
  • Annick Desjardins
    • 2
  • Katherine Peters
    • 2
  • Sridharan Gururangan
    • 1
    • 3
  • John H. Sampson
    • 1
  • Jennifer Marcello
    • 5
  • James E. HerndonII
    • 5
  • Roger E. McLendon
    • 6
  • Dorothea Janney
    • 1
  • Allan H. Friedman
    • 1
  • Darell D. Bigner
    • 6
  • Henry S. Friedman
    • 1
    • 3
  1. 1.Department of SurgeryDuke University Medical CenterDurhamUSA
  2. 2.Department of NeurologyDuke University Medical CenterDurhamUSA
  3. 3.Department of PediatricsDuke University Medical CenterDurhamUSA
  4. 4.Department of MedicineDuke University Medical CenterDurhamUSA
  5. 5.Department of Cancer Center BiostatisticsDuke University Medical CenterDurhamUSA
  6. 6.Department of PathologyDuke University Medical CenterDurhamUSA
  7. 7.The Brain Tumor Center at DukeDuke University Medical CenterDurhamUSA

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