"are doses and schedules of small molecule targeted anticancer drugs recommended by phase i studies realistic?"

"ARE DOSES AND SCHEDULES OF SMALL MOLECULE TARGETED ANTICANCER DRUGS RECOMMENDED BY PHASE I STUDIES REALISTIC?" Clin Cancer Res. 2015 Nov 18; Authors: Roda D, Jimenez B, Banerji U Abstract Tolerability of molecularly targeted agents (MTA) used in cancer therapeutics are determined in phase I trials. We reviewed the reported incidence of toxicity in phase III trials at doses and schedules recommended by phase I trials to evaluate if these recommendations are realistic when drugs are used in larger populations of patients. We systematically reviewed a safety profile of small molecule (SM-MTA) and monoclonal antibody MTA (MA-MTA) approved by the FDA in the last twelve years. There was a significantly increased percentage of grade 3 or 4 adverse events reported with SM-MTA compared to MA-MTA (40% v 27%, RR 1.5, 95% CI 1.10-2.25 p=0.038) in phase III studies. Importantly, a substantial proportion of patients (45%) treated with SM-MTA required dose modifications due to drug related toxicity in phase III trials. However this toxicity was associated to a definitive study drug discontinuation in only 9%. Overall 25% of SM-MTA declared recommended phase 2 doses below MTD based on pharmacokinetic-pharmacodynamic data and these trials were associated with a significantly reduced number of dose modifications in registration trials (32% vs 50%, RR: 0.64 95% CI 0.43-0.88, p=0.01). Tolerability is going to come into further focus due to the need for...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research