Advertisement

Journal of Neuro-Oncology

, Volume 90, Issue 1, pp 89–97 | Cite as

Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma

  • J. F. de Groot
  • M. R. Gilbert
  • K. Aldape
  • K. R. Hess
  • T. A. Hanna
  • S. Ictech
  • M. D. Groves
  • C. Conrad
  • H. Colman
  • V. K. Puduvalli
  • V. Levin
  • W. K. A. Yung
clinical-patient studies

Abstract

Targeting the epidermal growth factor receptor (EGFR) may be effective in a subset of glioblastoma patients. This phase II study assessed the clinical activity of erlotinib plus carboplatin and to determine molecular predictors of response. The primary endpoint was progression free survival (PFS). Patients with recurrent glioblastoma with no more than two prior relapses received carboplatin intravenously on day 1 of every 28-day cycle (target AUC of 6 mg × ml/min). Daily erlotinib at 150 mg/day was dose escalated to 200 mg/day, as tolerated. Clinical and MRI assessments were made every 4 and 8 weeks, respectively. Tumor tissue was evaluated for EGFR, AKT and phosphatase and tensin homolog (PTEN) status. One partial response (PR) was observed out of 43 assessable patients. Twenty patients (47%) had stable disease (SD) for an average of 12 weeks. Median PFS was 9 weeks. The 6-month PFS rate was 14%. Median overall survival (OS) was 30 weeks. This regimen was well tolerated with grade 3/4 toxicities of fatigue, leukopenia, thrombocytopenia and rash requiring dose reductions. A recursive partitioning analysis (RPA) predicted that patients with KPS ≥90 treated with more than 1 prior regimen had the highest OS. No correlation was observed between EGFR, Akt or PTEN expression and either PFS or OS. Carboplatin plus erlotinib is well tolerated but has modest activity in unselected patients. Future trials should be stratified based on optimal molecular or clinical characteristics.

Keywords

EGFR PTEN Erlotinib Carboplatin Glioblastoma 

References

  1. 1.
    Baselga J (2004) Combining the anti-EGFR agent gefitinib with chemotherapy in non-small-cell lung cancer: how do we go from INTACT to impact? J Clin Oncol 22:759–761CrossRefPubMedGoogle Scholar
  2. 2.
    Baselga J, Arteaga CL (2005) Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 23:2445–2459CrossRefPubMedGoogle Scholar
  3. 3.
    Carson KA, Grossman SA, Fisher JD, Shaw EG (2007) Prognostic factors for survival in adult patients with recurrent glioma enrolled onto the new approaches to brain tumor therapy CNS consortium phase I and II clinical trials. J Clin Oncol 25:2601–2606CrossRefPubMedGoogle Scholar
  4. 4.
    Cloughesy T, Yung WA, Vredenberg K et al (2005) Phase II study of erlotinib in recurrent GBM: molecular predictors of outcome. Am Soc Clin Oncol Annu Meet 23:1507Google Scholar
  5. 5.
    Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345CrossRefPubMedGoogle Scholar
  6. 6.
    Doz F, Berens ME, Dougherty DV, Rosenblum ML (1991) Comparison of the cytotoxic activities of cisplatin and carboplatin against glioma cell lines at pharmacologically relevant drug exposures. J Neurooncol 11:27–35CrossRefPubMedGoogle Scholar
  7. 7.
    Fuller GN, Bigner SH (1992) Amplified cellular oncogenes in neoplasms of the human central nervous system. Mutat Res 276:299–306PubMedGoogle Scholar
  8. 8.
    Grunwald V, Hidalgo M (2003) Development of the epidermal growth factor receptor inhibitor Tarceva (OSI-774). Adv Exp Med Biol 532:235–246PubMedGoogle Scholar
  9. 9.
    Haas-Kogan DA, Prados MD, Lamborn KR, Tihan T, Berger MS, Stokoe D (2005) Biomarkers to predict response to epidermal growth factor receptor inhibitors. Cell Cycle 4:1369–1372CrossRefPubMedGoogle Scholar
  10. 10.
    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 (2005) 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 23:5892–5899CrossRefPubMedGoogle Scholar
  11. 11.
    Kleihues P, Cavenee WK (eds) (2000) Pathology and genetics of tumors of the nervous system, 2nd edn. IARC Press, Lyon, FranceGoogle Scholar
  12. 12.
    Lassman AB, Rossi MR, Raizer JJ, 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
  13. 13.
    Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313:144–147CrossRefPubMedGoogle Scholar
  14. 14.
    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
  15. 15.
    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
  16. 16.
    Moyer JD, Barbacci EG, Iwata KK, Arnold L, Boman B, Cunningham A, DiOrio C, Doty J, Morin MJ, Moyer MP, Neveu M, Pollack VA, Pustilnik LR, Reynolds MM, Sloan D, Theleman A, Miller P (1997) Induction of apoptosis and cell cycle arrest by CP-358, 774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838–4848PubMedGoogle Scholar
  17. 17.
    Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H, Woo SY, Heimberger AB, Suki D, Prados MD, Chang SM, Barker FG 2nd, Buckner JC, James CD, Aldape K (2007) Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 25:2288–2294CrossRefPubMedGoogle Scholar
  18. 18.
    Pollack VA, Savage DM, Baker DA, Tsaparikos KE, Sloan DE, Moyer JD, Barbacci EG, Pustilnik LR, Smolarek TA, Davis JA, Vaidya MP, Arnold LD, Doty JL, Iwata KK, Morin MJ (1999) Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358, 774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739–748PubMedGoogle Scholar
  19. 19.
    Prados MD, Warnick RE, Mack EE, Chandler KL, Rabbitt J, Page M, Malec M (1996) Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial. Am J Clin Oncol 19:609–612CrossRefPubMedGoogle Scholar
  20. 20.
    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
  21. 21.
    Raizer J, Abrey LE, Wen T et al (2004) A phase II trial of erlotinib (OSI-774) in patients with recurrent malignant gliomas (MG) not on EIAEDs. Am Soc Clin Oncol Annu Meet 22:1502Google Scholar
  22. 22.
    Rich JN, Rasheed BK, Yan H (2004) EGFR mutations and sensitivity to gefitinib. N Engl J Med 351:1260–1261 author reply 1260–1261CrossRefPubMedGoogle Scholar
  23. 23.
    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
  24. 24.
    Shaw E, Arusell R, Scheithauer B, O’Fallon J, O’Neill B, Dinapoli R, Nelson D, Earle J, Jones C, Cascino T, Nichols D, Ivnik R, Hellman R, Curran W, Abrams R (2002) Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol 20:2267–2276CrossRefPubMedGoogle Scholar
  25. 25.
    Simmons ML, Lamborn KR, Takahashi M, Chen P, Israel MA, Berger MS, Godfrey T, Nigro J, Prados M, Chang S, Barker FG 2nd, Aldape K (2001) Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients. Cancer Res 61:1122–1128PubMedGoogle Scholar
  26. 26.
    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
  27. 27.
    Sugawa N, Ekstrand AJ, James CD, Collins VP (1990) Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci USA 87:8602–8606CrossRefPubMedGoogle Scholar
  28. 28.
    Sugawa N, Yamamoto K, Ueda S, Morita N, Kita M, Nishino H, Fushiki S, Okabe T (1998) Function of aberrant EGFR in malignant gliomas. Brain Tumor Pathol 15:53–57CrossRefPubMedGoogle Scholar
  29. 29.
    Van Den Bent M, Brandes A, Rampling R, Kouwenhoven M, Kros JM, Carpentier AF, Clement P, Klughammer B, Gorlia T, Lacombe D (2007) Randomized phase II trial of erlotinib (E) versus temozolomide (TMZ) or BCNU in recurrent glioblastoma multiforme (GBM): EORTC 26034. Proc Am Soc Clin Oncol 25:2005Google Scholar
  30. 30.
    Vogelbaum MA, Peereboom DM, Stevens G et al (2005) Phase II study of erlotinib single agent therapy in recurrent glioblastoma. Eur J Cancer Suppl 3:135Google Scholar
  31. 31.
    Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6:217–223 discussion 223–214CrossRefPubMedGoogle Scholar
  32. 32.
    Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84:6899–6903CrossRefPubMedGoogle Scholar
  33. 33.
    Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89:2965–2969CrossRefPubMedGoogle Scholar
  34. 34.
    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

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • J. F. de Groot
    • 1
  • M. R. Gilbert
    • 1
  • K. Aldape
    • 2
  • K. R. Hess
    • 3
  • T. A. Hanna
    • 1
  • S. Ictech
    • 1
  • M. D. Groves
    • 1
  • C. Conrad
    • 1
  • H. Colman
    • 1
  • V. K. Puduvalli
    • 1
  • V. Levin
    • 1
  • W. K. A. Yung
    • 1
  1. 1.Department of Neuro-OncologyUniversity of Texas – M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of PathologyUniversity of Texas – M.D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of BiostatisticsUniversity of Texas – M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations