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

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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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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Correspondence toBrian 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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