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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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References

  1. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  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 353:2012–2024

    Article  Google Scholar 

  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 97:880–887

    Article  CAS  PubMed  Google Scholar 

  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 21:6255–6263

    Article  CAS  PubMed  Google Scholar 

  5. Levin VA, Crafts DC, Norman DM et al (1977) Criteria for evaluating patients undergoing chemotherapy for malignant brain tumours. J Neurosurg 47:329–335

    Article  CAS  PubMed  Google Scholar 

  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 831:169–175

    Article  CAS  Google Scholar 

  7. Beal SL, Sheiner LB (1998) NONMEM users’ guide part I–VIII

  8. D’Argenio DZ, Schumitzky A (1990) ADAPT II user’s guide, 1st edn. Biomedical Simulations Resource, University of Southern California, Los Angeles

  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 12:327–331

    CAS  Google Scholar 

  10. Lee SJ, Goldstein JA (2005) Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics 6:357–371

    Article  CAS  PubMed  Google Scholar 

  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 63:765–770

    Article  CAS  PubMed  Google Scholar 

  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 21:2237–2246

    Article  CAS  PubMed  Google Scholar 

  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 344:783–792

    Article  CAS  PubMed  Google Scholar 

  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 353:1659–1672

    Article  CAS  PubMed  Google Scholar 

  15. Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684

    Article  CAS  PubMed  Google Scholar 

  16. Rich JN, Reardon DA, Peery T et al (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142

    Article  CAS  PubMed  Google Scholar 

  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 8:67–78

    Article  CAS  PubMed  Google Scholar 

  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)

  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 22

  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)

  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)

  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)

  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 64:6652–6659

    Article  CAS  PubMed  Google Scholar 

  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)

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Acknowledgments

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).

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Authors and Affiliations

  1. BC Cancer Agency, 600W 10th Ave, Vancouver, BC, V5Z 4E6, Canada

    Brian Thiessen

  2. St. Jude’s Children’s Research Hospital, Memphis, TN, USA

    Clinton Stewart & Paula Schaiquevich

  3. Princess Margaret Hospital, Toronto, ON, Canada

    Ming Tsao, Suzanne Kamel-Reid & Warren Mason

  4. Clark H. Smith Brain Tumor Center and Tom Baker Cancer Center, Calgary, AB, Canada

    Jacob Easaw & Peter Forsyth

  5. CHUM-Hopital Notre Dame, Montreal, QC, Canada

    Karl Belanger

  6. Clinical Trials Group, National Cancer Institute of Canada, Kingston, ON, Canada

    Lynn McIntosh & Elizabeth Eisenhauer

Authors
  1. Brian Thiessen
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  2. Clinton Stewart
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  3. Ming Tsao
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  4. Suzanne Kamel-Reid
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  5. Paula Schaiquevich
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  6. Warren Mason
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  7. Jacob Easaw
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  8. Karl Belanger
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  9. Peter Forsyth
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  10. Lynn McIntosh
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  11. Elizabeth Eisenhauer
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Corresponding author

Correspondence to Brian Thiessen.

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Thiessen, B., Stewart, C., Tsao, M. et al. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother Pharmacol 65, 353–361 (2010). https://doi.org/10.1007/s00280-009-1041-6

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  • DOI: https://doi.org/10.1007/s00280-009-1041-6

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