PURPOSE: Chloroquinoxaline sulfonamide (CQS) was one of the first agents identified by the human tumor colony-forming assay (HTCFA) as possessing antitumor activity in non-small-cell lung cancer (NSCLC). Prior phase I studies had suggested that plasma concentrations equivalent to those showing efficacy in the HTCFA could be reliably attained in humans. This phase II study assessed the antitumor activity of CQS while using an adaptive control pharmacokinetic modelling system to attain targeted plasma levels of this novel compound. METHODS: A group of 20 patients with stage III or IV NSCLC received CQS as a 1-h weekly infusion at an initial dose of 2 g/m2. In all patients, 24-h plasma concentrations of CQS were measured. Patients with levels < 100 micrograms/ml had dose increases determined by their 24-h levels and pharmacokinetic parameters obtained from two prior phase I trials of this agent. These individuals had 24-h CQS levels repeated after their second weeks' treatment and doses were readjusted if the target concentration was not reached. Antitumor response assessment was made every 6 weeks. RESULTS: Of the 20 patients, 18 attained the target plasma concentration, and 16 of these achieved this initially or with just one dose adjustment. No major objective antitumor responses were observed (major response rate 0%, 95% CI 0-17%). CQS was well tolerated with hypoglycemia being the most clinically significant toxicity. CONCLUSIONS: When given on this schedule CQS is inactive in NSCLC despite the fact that the target concentration was achieved in 90% of patients. The ability of the HTCFA to identify active agents remains unproved.
PURPOSE:Chloroquinoxaline sulfonamide (CQS) was one of the first agents identified by the humantumor colony-forming assay (HTCFA) as possessing antitumor activity in non-small-cell lung cancer (NSCLC). Prior phase I studies had suggested that plasma concentrations equivalent to those showing efficacy in the HTCFA could be reliably attained in humans. This phase II study assessed the antitumor activity of CQS while using an adaptive control pharmacokinetic modelling system to attain targeted plasma levels of this novel compound. METHODS: A group of 20 patients with stage III or IV NSCLC received CQS as a 1-h weekly infusion at an initial dose of 2 g/m2. In all patients, 24-h plasma concentrations of CQS were measured. Patients with levels < 100 micrograms/ml had dose increases determined by their 24-h levels and pharmacokinetic parameters obtained from two prior phase I trials of this agent. These individuals had 24-h CQS levels repeated after their second weeks' treatment and doses were readjusted if the target concentration was not reached. Antitumor response assessment was made every 6 weeks. RESULTS: Of the 20 patients, 18 attained the target plasma concentration, and 16 of these achieved this initially or with just one dose adjustment. No major objective antitumor responses were observed (major response rate 0%, 95% CI 0-17%). CQS was well tolerated with hypoglycemia being the most clinically significant toxicity. CONCLUSIONS: When given on this schedule CQS is inactive in NSCLC despite the fact that the target concentration was achieved in 90% of patients. The ability of the HTCFA to identify active agents remains unproved.
Authors: T H Corbett; P LoRusso; L Demchick; C Simpson; S Pugh; K White; J Kushner; L Polin; J Meyer; J Czarnecki; L Heilbrun; J P Horwitz; J L Gross; C H Behrens; B A Harrison; R J McRipley; G Trainor Journal: Invest New Drugs Date: 1998 Impact factor: 3.850