title: Phase I trials of molecularly targeted agents: should we pay more attention to late toxicities?
abstract: OBJECTIVE
  Phase I trials traditionally aim at determining the recommended phase II dose (RP2D) using grade ≥ 3 toxicity data from cycle 1 (C1) only. This design dates from the era of conventional chemotherapy and may not be relevant for new molecularly targeted agents (MTAs) usually administered in a chronic fashion and for which late or moderate toxicities may deserve particular attention.
  
  
  METHODS
  All consecutive patients treated in phase I trials of MTAs at the Royal Marsden Hospital and Institut Gustave Roussy between January 2005 and July 2008 were included. Gastrointestinal, skin, and clinical renal toxicities of any grade and grades 3 to 4 toxic events of any type occurring at any cycle on treatment were recorded. Doses administered, treatment interruptions, dose modifications, and prescription of comedications were analyzed.
  
  
  RESULTS
  A total of 445 patients (1,566 cycles; median treatment duration, 55 days) were included in 36 eligible trials; 790 toxicities (590, grade 1; 176, grade, 2; 24 grades, 3 to 4) and 1,819 toxicities (1,521, grade 1; 265, grade 2; 33, grades 3 to 4) were recorded during and after C1, respectively; 57% of the grades 3 to 4 toxicities occurred after C1; 50% of patients presented their worst-grade toxicity after C1. The risk of grades 3 to 4 toxicity was 3% in cycles 1 to 6 and was almost null afterwards. No cumulative toxicities were observed. Median toxicity duration was 15 days, with comedication administered in 68% of events.
  
  
  CONCLUSIONS
  Moderate and severe toxicities occur regularly after the first cycle in phase I trials of MTAs and may deserve increased attention in the RP2D process for these agents.
authors: Royal Marsden Hospital and The Institute of Cancer Research, Sutton, United Kingdom.
authors: Sophie
authors: S
authors: Postel-Vinay
authors: Carlos
authors: C
authors: Gomez-Roca
authors: L Rhoda
authors: LR
authors: Molife
authors: Bhavesh
authors: B
authors: Anghan
authors: Antonin
authors: A
authors: Levy
authors: Ian
authors: I
authors: Judson
authors: Johann
authors: J
authors: De Bono
authors: Jean-Charles
authors: JC
authors: Soria
authors: Stan
authors: S
authors: Kaye
authors: Xavier
authors: X
authors: Paoletti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000009:adverse effects*; D012867:Skin / Q000187:drug effects; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents