Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 2, pp 353–361 | Cite as

A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation

  • Brian ThiessenEmail author
  • Clinton Stewart
  • Ming Tsao
  • Suzanne Kamel-Reid
  • Paula Schaiquevich
  • Warren Mason
  • Jacob Easaw
  • Karl Belanger
  • Peter Forsyth
  • Lynn McIntosh
  • Elizabeth Eisenhauer
Original Article



We undertook a phase I/II study of the EGFR/erbB2 inhibitor lapatinib in patients with recurrent glioblastoma multiforme (GBM) to determine response rate, pharmacokinetics (PK) and recommended dose in patients taking enzyme-inducing anti-epileptic drugs (EIAEDs) and to explore relationships of molecular genetics to outcome.


Recurrent GBM patients taking EIAEDs were enrolled on the phase I portion (starting dose of lapatinib 1,000 mg po bid). In the absence of dose-limiting toxicity (DLT), escalation continued in cohorts of three patients. Patients not on EIAEDs enrolled in the phase II arm (lapatinib 750 mg bid po). Immunohistochemical and quantitative RT PCR studies were performed on tumor to determine PTEN and EGFRvIII status, respectively. Lapatinib PK was analyzed using HPLC with tandem mass spectrometry.


Phase II: Of 17 patients, 4 had stable disease and 13 progressed. Accrual ceased because of no responses. Phase I: Four patients received 1,000 mg bid and three, 1,500 mg bid. No DLT occurred, but escalation stopped because of lack of phase II efficacy. Lapatinib apparent oral clearance in patients taking EIAEDs was 106.9 L h−1 m−2 in comparison to 12.1 L h−1 m−2 in those not on EIAEDs. In 16 phase II patients, PTEN loss was seen in 6 and EGFRvIII expression in 4. No correlation was seen with outcome and molecular results.


Lapatinib apparent oral clearance increased by approximately tenfold when given with EIAEDs. In this small sample, EGFRvIII expression and PTEN loss did not predict a favorable subtype. Overall, lapatinib did not show significant activity in GBM patients.


Lapatinib Glioblastoma Pharmacokinetics Clinical trial 



This study was supported by a grant from the National Cancer Institute of Canada with funding provided by the Canadian Cancer Society. Lapatnib was provided by NCI US (Cancer Therapy Evaluation Program).


  1. 1.
    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  2. 2.
    Melinghoff IK, Wang MY, Vivanco I et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. New Engl J Med 353:2012–2024CrossRefGoogle Scholar
  3. 3.
    Haas-Kogan DA, Prados MD, Tihan T et al (2005) Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 97:880–887PubMedCrossRefGoogle Scholar
  4. 4.
    Xia W, Mullin RJ, Keith BR et al (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of the EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21:6255–6263CrossRefPubMedGoogle Scholar
  5. 5.
    Levin VA, Crafts DC, Norman DM et al (1977) Criteria for evaluating patients undergoing chemotherapy for malignant brain tumours. J Neurosurg 47:329–335CrossRefPubMedGoogle Scholar
  6. 6.
    Bai F, Freeman BB III, Fraga CH et al (2006) Determination of lapatinib (GW572016) in human plasma by liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS). J Chromatogr B Anal Technol Biomed Life Sci 831:169–175CrossRefGoogle Scholar
  7. 7.
    Beal SL, Sheiner LB (1998) NONMEM users’ guide part I–VIIIGoogle Scholar
  8. 8.
    D’Argenio DZ, Schumitzky A (1990) ADAPT II user’s guide, 1st edn. Biomedical Simulations Resource, University of Southern California, Los AngelesGoogle Scholar
  9. 9.
    Kadlubar FF, Berkowitz GS, Delongchamp RR et al (2003) The CYP3A4*1B variant is related to the onset of puberty, a known risk factor for the development of breast cancer. Cancer Epidemiol Biomark Prev 12:327–331Google Scholar
  10. 10.
    Lee SJ, Goldstein JA (2005) Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics 6:357–371CrossRefPubMedGoogle Scholar
  11. 11.
    Zheng H, Webber S, Zeevi A et al (2002) The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients. Hum Immunol 63:765–770CrossRefPubMedGoogle Scholar
  12. 12.
    Fukuoka M, Yano S, Giaccone G et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer (The IDEAL 1 trial). J Clin Oncol 21:2237–2246CrossRefPubMedGoogle Scholar
  13. 13.
    Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New Engl J Med 344:783–792CrossRefPubMedGoogle Scholar
  14. 14.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672CrossRefPubMedGoogle Scholar
  15. 15.
    Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684CrossRefPubMedGoogle Scholar
  16. 16.
    Rich JN, Reardon DA, Peery T et al (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142CrossRefPubMedGoogle Scholar
  17. 17.
    Prados MD, Lamborn KR, Chang S et al (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
  18. 18.
    Blackwell KL, Kaplan EH, Franco SX et al (2004) A phase II, open label, multicenter study of GW572016 in patients with trastuzumab-refractory metastatic breast cancer. J Clin Oncol 23(14 Suppl)Google Scholar
  19. 19.
    Kaplan EH, Jones CM, Berger MS (2003) A phase II, open label, multicenter study of GW572016 in patients with trastuzumab refractory metastatic breast cancer. Proc Am Soc Clin Oncol 22Google Scholar
  20. 20.
    Burstein H, Storniolo AM, Franco S et al (2004) A phase II, open label, multicenter study of lapatinib in two cohorts of patients with advanced or metastatic breast cancer who have progressed while receiving trastuzumab-containing regimens. Ann Oncol 15(Suppl 3)Google Scholar
  21. 21.
    Blackwell KL, Burstein H, Pegram M et al (2005) Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab refractory metastatic breast cancer. J Clin Oncol 23(16 Suppl)Google Scholar
  22. 22.
    Perez EA, Byrne JA, Hammond IW et al (2006) Results of an analysis of cardiac function in 2,812 patients treated with lapatinib. J Clin Oncol 24(18 Suppl)Google Scholar
  23. 23.
    Wood ER, Truesdale AT, McDonald OB et al (2004) A unique structure for epidermal growth factor bound to GW572016 (lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64:6652–6659CrossRefPubMedGoogle Scholar
  24. 24.
    Lin NU, Carey La, Liu MC et al (2006) Phase II trial of lapatinib for brain metastases in patients with HER2 + breast cancer. J Clin Oncol 23(16 Suppl)Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Brian Thiessen
    • 1
    Email author
  • Clinton Stewart
    • 2
  • Ming Tsao
    • 3
  • Suzanne Kamel-Reid
    • 3
  • Paula Schaiquevich
    • 2
  • Warren Mason
    • 3
  • Jacob Easaw
    • 4
  • Karl Belanger
    • 5
  • Peter Forsyth
    • 4
  • Lynn McIntosh
    • 6
  • Elizabeth Eisenhauer
    • 6
  1. 1.BC Cancer AgencyVancouverCanada
  2. 2.St. Jude’s Children’s Research HospitalMemphisUSA
  3. 3.Princess Margaret HospitalTorontoCanada
  4. 4.Clark H. Smith Brain Tumor Center and Tom Baker Cancer CenterCalgaryCanada
  5. 5.CHUM-Hopital Notre DameMontrealCanada
  6. 6.Clinical Trials GroupNational Cancer Institute of CanadaKingstonCanada

Personalised recommendations