NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas

Lieberman, Frank S.; Cloughesy, Tim; Fine, Howard A.; Kuhn, John G.; Lamborn, Kathleen R.; Malkin, Mark G.; Robbins, H. I.; Yung, W. A.; Wen, Ping; Prados, M.

doi:10.1200/jco.2004.22.14_suppl.1510

Cited by 36 publications

(13 citation statements)

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“…We observed that patients receiving EIAED has significantly lower peak concentrations and exposure (AUC 0-24 ) to gefitinib compared to the non-EIAED patients. This observation is consistent with another recent report [16] and our NABTC 00-01 phase-1 single-dose trial with gefitinib alone in patients with recurrent malignant gliomas [10]. In the NABTC 00-01 trial, patients on EIAEDs received escalating doses of gefitinib ranging from 500 to 2,000 mg daily.…”

Section: Discussionsupporting

confidence: 80%

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

Prados

Yung

Wen

et al. 2007

Cancer Chemother Pharmacol

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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 enzymeinducing 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/m 2 /day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m 2 /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 AUC 0-24hr 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.

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Section: Discussionsupporting

confidence: 80%

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

Prados

Yung

Wen

et al. 2007

Cancer Chemother Pharmacol

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“…Similar findings were observed in a second phase II study (75). Another phase I-II trial that was conducted by the North American Brain Tumor Consortium showed partial response in 13% of recurrent glioblastoma and 12% of recurrent anaplastic glioma in patients receiving prior radiotherapy (76). Noteworthy, no correlation was found between clinical response and HER1/ EGFR gene amplification or EGFRvIII mutation for either gefitinib or erlotinib (71,(73)(74)(75).…”

Section: Small-molecule Tk Inhibitorssupporting

confidence: 61%

Therapeutic Inhibition of the Epidermal Growth Factor Receptor in High-Grade Gliomas: Where Do We Stand?

Karpel‐Massler¹,

Schmidt²,

Unterberg³

et al. 2009

Molecular Cancer Research

115

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“…Moreover, recent studies have demonstrated that EGFRvIII is required for tumor maintenance in glioma (Mukasa et al, 2010). The EGFR tyrosine kinase inhibitor gefitinib has been evaluated in a number of clinical trials for GBM; however, results have been disappointing (Rich et al, 2004;Lieberman et al, 2004). The failure of gefitinib raises questions pertaining to delivery of drug to its target.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Gefitinib to the Brain Is Limited by P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2)-Mediated Active Efflux

Agarwal

Sane

Gallardo

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

220

195

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Gefitinib is an orally active inhibitor of the epidermal growth factor receptor approved for use in patients with locally advanced or metastatic non-small cell lung cancer. It has also been evaluated in several clinical trials for treatment of brain tumors such as high-grade glioma. In this study, we investigated the influence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on distribution of gefitinib to the central nervous system. In vitro studies conducted in MadinDarby canine kidney II cells indicate that both P-gp and BCRP effectively transport gefitinib, limiting its intracellular accumulation. In vivo studies demonstrated that transport of gefitinib across the blood-brain barrier (BBB) is significantly limited. Steady-state brain-to-plasma (B/P) concentration ratios were 70-fold higher in the Mdr1a/b(Ϫ/Ϫ) Bcrp1(Ϫ/Ϫ) mice (ratio of approximately 7) compared with wild-type mice (ratio of approximately 0.1). The B/P ratio after oral administration increased significantly when gefitinib was coadministered with the dual P-gp and BCRP inhibitor elacridar. We investigated the integrity of tight junctions in the Mdr1a/b(Ϫ/Ϫ) Bcrp1(Ϫ/Ϫ) mice and found no difference in the brain inulin and sucrose space between the wild-type and Mdr1a/b(Ϫ/Ϫ) Bcrp1(Ϫ/Ϫ) mice. This suggested that the dramatic enhancement in the brain distribution of gefitinib is not due to a leakier BBB in these mice. These results show that brain distribution of gefitinib is restricted due to active efflux by P-gp and BCRP. This finding is of clinical significance for therapy in brain tumors such as glioma, where concurrent administration of a dual inhibitor such as elacridar can increase delivery and thus enhance efficacy of gefitinib.Malignant gliomas account for approximately 70% of all new cases of malignant primary brain tumors diagnosed in the United States every year. Glioblastoma multiforme (GBM) is the most common type of glioma, accounting for approximately 60 to 70% of malignant gliomas (Wen and Kesari, 2008; CBTRUS, 2008) and claiming 12,000 lives every year (Davis et al., 2001). Epidermal growth factor receptor (EGFR) and its variant EGFRvIII play a critical role in the development of an aggressive phenotype of GBM; EGFR amplification, mutation, and overexpression are associated with poor prognosis and resistance to therapy (Brandes et al., 2008). Several therapeutic strategies targeting EGFR in GBM have been proposed, including the use of monoclonal antibodies against EGFR or EGFRvIII, vaccine therapies, bispecific antibodies, toxin-linked conjugates, and small molecule tyrosine kinase inhibitors (Omuro et al., 2007).

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NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas

Cited by 36 publications

References 0 publications

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

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

Therapeutic Inhibition of the Epidermal Growth Factor Receptor in High-Grade Gliomas: Where Do We Stand?

Distribution of Gefitinib to the Brain Is Limited by P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2)-Mediated Active Efflux

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