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| |  Experimental Drug Exhibits Marked Anti-Tumour Activity LA JOLLA, CA -- June 17, 1998 -- Results from two phase I studies and one preclinical study of Agouron Pharmaceuticals, Inc.’s oral anti-angiogenesis drug, AG3340 show the drug exhibits marked anti-tumour activity. The data were reported today at the 10th European Organization for Research and Treatment of Cancer (EORTC) meeting in Amsterdam, The Netherlands. In a phase I safety and tolerability study of AG3340 administered orally twice daily (BID) in patients with advanced cancer, including lung, prostate, kidney and colorectal cancers as well as sarcoma and melanoma, disease was stabilised in more than 25% of 47 evaluable patients who were treated for periods of 16 to 40 weeks. Either two or three patients in each of five small dosing groups (5mg, 10mg, 25mg, 50mg and 100mg BID) comprising the 47 patients experienced stable disease. Three patients (one each with non-small cell lung cancer, renal carcinoma and melanoma) were found to have minor reductions in tumour volume. Nine other evaluable patients in two additional dosing groups (1mg and 2mg BID) had not yet received 16 weeks of treatment and are still under evaluation. AG3340 was found to be generally well tolerated in this study. Expected musculoskeletal side effects, including arthralgias and body aches, occurred less frequently at doses below 25mg BID and were managed effectively by a rest from treatment followed by a dose reduction. Based on the safety and tolerability data from this study, pivotal phase II/III clinical trials have been initiated using AG3340 in 5mg, 10mg, and l5mg doses given BID in combination with standard chemotherapy in patients with advanced non-small cell lung cancer or advanced hormone-refractory prostate cancer. A separate phase I study found that AG3340 in combination with chemotherapy was generally well tolerated among patients with advanced prostate cancer who were resistant to hormonal therapies. This study evaluated the use of AG3340 -- in a dose of 25 mg BID -- in combination with Novantrone(R) (mitoxantrone) plus prednisone in 15 patients with advanced prostate cancer. In this ongoing study, nine patients have received the combination treatment for more than ten weeks; seven patients have received treatment for more than 18 weeks. Pharmacokinetic analysis of the available data confirmed that AG3340 blood levels are not affected by administration with mitoxantrone. No unexpected side effects occurred in the patients in this study. In a separate preclinical study, AG3340 was found to be a potent inhibitor of the growth of chemotherapy-resistant human non-small cell lung cancer tumours in mice. Here, administration of AG3340 resulted in a dose-dependent decrease in tumour growth by up to 65% as compared to controls. Paraplatin(R) (carboplatin), a currently available chemotherapeutic agent, demonstrated a similar amount of anti-tumour effect at toxic doses, whereas AG3340 inhibited growth at well-tolerated doses. The study also demonstrated that the combination of carboplatin and AG3340 was more effective than either agent alone, suggesting that the combination of the two drugs could provide beneficial clinical results. A key action of AG3340 was also demonstrated by finding a 77% reduction in the formation of new tumour-associated blood vessels. Neovascularization, or new blood vessel formation (angiogenesis), is required to support growing tumours. AG3340 is an orally active, synthetic molecule designed to inhibit the growth, invasion and metastasis of solid tumours by inactivating certain members of a family of enzymes known as matrix metalloproteases (MMPs). AG3340 selectively inhibits those MMPs believed to be involved in tumour progression. A primary goal of the clinical studies of AG3340 is to determine whether this distinctive selectivity results in a favourable clinical profile of safety and efficacy.
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