ZD1839, a Selective Oral Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor, Is Well Tolerated and Active in Patients With Solid, Malignant Tumors: Results of a Phase I Trial

Abstract

ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.

Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells

“…In addition, human breast cancer cells overexpressing HER2 or acquiring resistance to the oestrogen receptor (ER) antagonist, fulvestrant (Faslodex,ICI 182,780), have been reported to be particularly sensitive to gefitinib (McClelland et al, 2001;Moulder et al, 2001). Furthermore, phase I trials of gefitinib in patients with solid tumours refractory to standard chemotherapies have shown good tolerability and promising antitumour activity Herbst et al, 2002;Ranson et al, 2002). These findings suggest that gefitinib will be clinically useful in the treatment of patients with hormone-refractory breast cancer.…”

Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA)

“…Phase I trials of gefitinib in patients with solid tumours refractory to standard chemotherapy have shown good tolerability and evidence of antitumour activity (Ferry et al, 2000;Ranson et al, 2002). IDEAL (IRESSA Dose Evaluation in Advanced Lung cancer) 1 and 2 were randomised phase II trials in patients with non-small-cell lung cancer (NSCLC) refractory to platinum-based chemotherapy.…”

Gefitinib (‘Iressa’, ZD1839) and new epidermal growth factor receptor inhibitors

“…Four multicentre, open-label, Phase I trials investigated the tolerability and efficacy of oral gefitinib (up to 1000 mg day À1 ) in patients with a variety of solid tumours, including NSCLC Ranson et al, 2002;Nakagawa et al, 2003). As gefitinib is not a traditional cytotoxic agent, dose selection for further study was based on identification of the optimum biological dose, combining maximum efficacy with minimum adverse events (AEs).…”

“…The maximum tolerated dose (MTD) was X700 mg day À1 . Promising antitumour activity was observed in a number of tumour types, particularly NSCLC; 10 out of 100 NSCLC patients experienced a partial tumour response Ranson et al, 2002;Nakagawa et al, 2003). Partial responses and disease stabilisation were observed at doses X150 mg day À1 with no suggestion that higher doses provided greater antitumour activity (Herbst and Kies, 2002;Ranson et al, 2002).…”