Cancer Chemotherapy and Pharmacology

, Volume 61, Issue 6, pp 1059–1067 | Cite as

Phase-1 trial of gefitinib and temozolomide in patients with malignant glioma: a North American brain tumor consortium study

  • Michael D. Prados
  • W. K. A. Yung
  • Patrick Y. Wen
  • Larry Junck
  • Timothy Cloughesy
  • Karen Fink
  • Susan Chang
  • H. Ian Robins
  • Janet Dancey
  • John Kuhn
Clinical Trial Report

Abstract

Purpose

This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide.

Patients and methods

Patients were stratified according to co-administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m2/day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m2/day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only.

Results

For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC0-24hr at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h.

Conclusion

The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs.

Keywords

Temozolomide Gefitinib Malignant gliomas Enzyme-inducing anti-epileptic drugs 

Notes

Acknowledgments

This study was supported by the following grants: NABTC grants: CA62399, CA62422, CA62412, U01CA62407-08, CA62455-08, U01CA62405, CA62426, U01CA62399 No. 022330 (for NABTC98-03 only), U01CA62399, 5-U01CA62399-09, U01CA62399-09, and U01CA62421-08. GCRC grants: M01-RR00079, CA16672, M01-RR00633, M01-RR00056, M01-RR0865, M01-RR00042, M01-RR03186.

References

  1. 1.
    Baker SD, Wirth M, Statkevich P, Reidenberg P, Alton K, Sartorius SE, Dugan M, Cutler D, Batra V, Grochow LB, Donehower RC, Rowinsky EK (1999) Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res 5:309–317PubMedGoogle Scholar
  2. 2.
    Begley DJ (2004) Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther 104:29–45PubMedCrossRefGoogle Scholar
  3. 3.
    Bigner SH, Humphrey PA, Wong AJ, Vogelstein B, Mark J, Friedman HS, Bigner DD (1990) Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res 50:8017–8022PubMedGoogle Scholar
  4. 4.
    Cappuzzo F, Calandri C, Bartolini S, Crino L (2003) ZD 1839 in patients with brain metastases from non-small-cell lung cancer (NSCLC): report of four cases. Br J Cancer 89:246–247PubMedCrossRefGoogle Scholar
  5. 5.
    Chakravarti A, Dicker A, Mehta M (2004) The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: a review of preclinical and correlative clinical data. Int J Radiat Oncol Biol Phys 58:927–931PubMedGoogle Scholar
  6. 6.
    Jones HK, Stafford LE, Swaisland HC, Payne R (2002) A sensitive assay for ZD1839 (Iressa) in human plasma by liquid-liquid extraction and high performance liquid chromatography with mass spectrometric detection: validation and use in Phase I clinical trials. J Pharm Biomed Anal 29:221–218PubMedCrossRefGoogle Scholar
  7. 7.
    Kitazaki T, Oka M, Nakamura Y, Tsurutani J, Doi S, Yasunaga M, Takemura M, Yabuuchi H, Soda H, Kohno S (2005) Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. Lung Cancer 49:337–343PubMedCrossRefGoogle Scholar
  8. 8.
    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 11:7841–7850PubMedCrossRefGoogle Scholar
  9. 9.
    Leuraud P, Taillandier L, Medioni J, Aguirre-Cruz L, Criniere E, Marie Y, Kujas M, Golmard JL, Duprez A, Delattre JY, Sanson M, Poupon MF (2004) Distinct responses of xenografted gliomas to different alkylating agents are related to histology and genetic alterations. Cancer Res 64:4648–4653PubMedCrossRefGoogle Scholar
  10. 10.
    Lieberman FS, Cloughesy T, Fine H, Kuhn J, Lamborn K, Malkin M, Robbins HI, Yung WA, Wen P, Prados M (2004) NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas. J Clin Oncol 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 22:108s [Abstract 1510]Google Scholar
  11. 11.
    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 (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139PubMedCrossRefGoogle Scholar
  12. 12.
    McKillop D, McCormick AD, Millar A, Miles GS, Phillips PJ, Hutchison M (2005) Cytochrome P450-dependent metabolism of gefitinib. Xenobiotica 35:39–50PubMedCrossRefGoogle Scholar
  13. 13.
    McKillop D, Partridge EA, Kemp JV, Spence MP, Kendrew J, Barnett S, Wood PG, Giles PB, Patterson AB, Bichat F, Guilbaud N, Stephens TC (2005) Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor. Mol Cancer Ther 4:641–649PubMedCrossRefGoogle Scholar
  14. 14.
    Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedCrossRefGoogle Scholar
  15. 15.
    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. Neurooncology 8:67–78Google Scholar
  16. 16.
    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 12:860–868PubMedCrossRefGoogle Scholar
  17. 17.
    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 22:133–142PubMedCrossRefGoogle Scholar
  18. 18.
    Stark AM, Witzel P, Strege RJ, Hugo HH, Mehdorn HM (2003) p53, mdm2, EGFR, and msh2 expression in paired initial and recurrent glioblastoma multiforme. J Neurol Neurosurg Psychiatry 74:779–783PubMedCrossRefGoogle Scholar
  19. 19.
    Stea B, Falsey R, Kislin K, Patel J, Glanzberg H, Carey S, Ambrad AA, Meuillet EJ, Martinez JD (2003) Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD1839 (‘Iressa’). Cancer Lett 202:43–51PubMedCrossRefGoogle Scholar
  20. 20.
    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 352:987–996PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Michael D. Prados
    • 1
  • W. K. A. Yung
    • 2
  • Patrick Y. Wen
    • 3
  • Larry Junck
    • 4
  • Timothy Cloughesy
    • 5
  • Karen Fink
    • 6
  • Susan Chang
    • 1
  • H. Ian Robins
    • 7
  • Janet Dancey
    • 8
  • John Kuhn
    • 9
  1. 1.Department of Neurological SurgeryUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Department of Neuro-OncologyUniversity of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Dana-Farber Cancer InstituteBostonUSA
  4. 4.Department of NeurologyUniversity of Michigan HospitalAnn ArborUSA
  5. 5.Department of NeurosurgeryUniversity of California Los AngelesLos AngelesUSA
  6. 6.Department of NeurologyUniversity of Texas, Southwestern Medical CenterDallasUSA
  7. 7.University of Wisconsin HospitalMadisonUSA
  8. 8.National Cancer Institute, National Institutes of HealthBethesdaUSA
  9. 9.Department of NeurologyUniversity of Texas, Southwestern Medical CenterDallasUSA

Personalised recommendations