Phase I studies of ZD1839 in patients with common solid tumors.
Clinical development of ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) was initiated based on strong preclinical studies that showed antitumor responses in a variety of solid tumor types and established its oral bioavailability and tolerability. In phase I trials, ZD1839 was investigated in patients with a wide variety of solid tumors that commonly express epidermal growth factor receptor-tyrosine kinase. More than 250 patients with advanced refractory disease were enrolled in phase I studies; of these, 100 had non-small cell lung cancer (NSCLC). All patients had been recipients of substantial prior therapy. Intermittent and continuous dosing schedules with ZD1839 were well tolerated by these patients for up to 6 months or more. The most frequently reported adverse events were grade 1 or 2 diarrhea and grade 1 or 2 acneiform rash; these effects were reversible on discontinuation of therapy and either required no management or were easily managed. Grade 3 or 4 adverse events were rare and most were attributed to disease progression rather than being drug related. In phase I trials, the maximum tolerated dose of ZD1839 was determined to be 700 to 1000 mg/day; diarrhea was found to be the dose-limiting toxicity. Pharmacokinetic profiles supported once-daily oral dosing and indicated that biologically active plasma concentrations were achieved at the doses studied. Pharmacodynamic results in skin biopsies showed that ZD1839 produced inhibition of epidermal growth factor receptor-tyrosine kinase in these patients. Durable tumor responses and stable disease were observed with ZD1839 treatment in patients with advanced NSCLC. Symptoms related to NSCLC also appeared to improve rapidly in some patients. Prolonged time on therapy was observed for other tumor types in addition to NSCLC, including hormone-refractory prostate, colorectal, head and neck, breast, ovarian, and renal cancers. The promising phase I results observed in heavily pretreated patients with advanced NSCLC and other solid tumors have warranted investigation in phase II/III clinical trials in these populations. Phase II/III trials are being conducted in patients with advanced NSCLC. Phase II trials of ZD1839 are also being conducted in patients who have hormone-refractory prostate, breast, or colorectal cancer, as well as other solid tumors. Based on the phase I study results, once-daily oral doses of 250 mg and 500 mg, which are well below the maximum tolerated dose, were selected for further clinical investigation of ZD1839.
Lorusso
Patricia M
PM
Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201-2097, USA.
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D017321:Clinical Trials, Phase I as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D009025:Morpholines / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009025:Morpholines; D011799:Quinazolines; C420268:Canertinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib