A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation
- 952 Downloads
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.
KeywordsLapatinib 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).
- 7.Beal SL, Sheiner LB (1998) NONMEM users’ guide part I–VIIIGoogle Scholar
- 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.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
- 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.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.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.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.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
- 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