Defining the risk of toxicity in phase I oncology trials of novel molecularly targeted agents: A single-center experience

Background: Phase I oncology trials are designed to define the maximum tolerated dose and toxicity of new drugs. This study aims to define the risk of toxicity in phase I trials of novel molecularly targeted agents (MTA), as this therapeutic approach is becoming increasingly relevant.Methods: We performed a retrospective analysis of toxicity data from all patients (p) treated in phase I trials. The primary aim was to define the rate of treatment-related grade (g) 3 and 4 toxicities and deaths associated with novel single agent MTAs.Results: 1,145 p were treated within a phase I trial between January 2005 and October 2009. Of these, 727 p were treated with novel MTAs; here we report on complete toxicity data from an initial 173 sequential p treated within 37 trials of agents targeting growth factor receptors, angiogenesis, cell cycle/apoptosis, cytoplasmic signaling proteins, chromatin remodeling/DNA repair, protein folding and degradation and oncolysis. The median age was 60 years (range 24-85); 88 female/85 male. 158 p were ECOG PS 0-1 and 15 PS 2. 40 g3 (rate 23%) and 3 g4 (rate 1.7%) treatment-related events occurred. There was 1 treatment-related death (mortality, 0.6%). 49% of all events were gastrointestinal in origin (nausea and diarrhea), 18% neurological (including fatigue), 13% cardiac (hypertension and ECG changes), and 2% (each) renal, respiratory and cutaneous. 42 of 43 (97.7%) events resolved with dose interruption or dose reduction.Conclusions: Therapy with novel MTAs in the phase I setting is associated with a moderate risk of significant toxicity, though this appears less than in phase I studies involving cytotoxic agents, particularly in relation to g4 toxicity (Horstmann et al, N Engl J Med 2005). The majority of these toxicities were easily managed with dose interruption/reduction. The risk of death is low and in line with that reported in other published series