title: Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents--dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study.
abstract: BACKGROUND
  Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention.
  
  
  METHODS
  In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded.
  
  
  RESULTS
  The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G ⩾ 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G⩾3 toxicity occurring after C1 in 18.6% of patients.
  
  
  CONCLUSIONS
  Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI.
authors.affiliation: Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), 114 rue Edouard Vaillant, 94800 Villejuif, France; Université Paris-Sud XI, 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France. Electronic address: Sophie.postel-vinay@gustaveroussy.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Postel-Vinay
authors.affiliation: EORTC Headquarters, Avenue Emmanuel Mounier 83/11, B-1200 Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Collette
authors.affiliation: Statistics Department and INSERM U900, Institut Curie, 126 rue d'Ulm, 75006 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
authors.affiliation: EORTC Headquarters, Avenue Emmanuel Mounier 83/11, B-1200 Brussels, Belgium.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rizzo
authors.affiliation: Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), 114 rue Edouard Vaillant, 94800 Villejuif, France; Université Paris-Sud XI, 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.affiliation: Department of Medical Oncology and INSERM U900, Institut Curie, 126 rue d'Ulm, 75006 Paris and St Cloud, France; Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernandez Almagro, 3, 28029 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.affiliation: Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Norte-Sanchinarro, Calle Oña 10, 28050 Madrid, Spain.
authors.forename: Camilla
authors.initials: C
authors.lastname: Fowst
authors.affiliation: Pfizer Oncology, Clinical Development, Pfizer Italia S.p.A., Via A.M. Mozzoni 12, Milan 20152, Italy.
authors.forename: Bernard
authors.initials: B
authors.lastname: Levy
authors.affiliation: Roche TCRC Inc., 430 East 29th StreetNew York, NY 10016, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mancini
authors.affiliation: EORTC Headquarters, Avenue Emmanuel Mounier 83/11, B-1200 Brussels, Belgium.
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Sanofi R&D, 13, quai Jules Guesde - BP 14, 94403 Vitry-sur-Seine Cedex, France.
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.affiliation: National Cancer Institute and Cancer Therapy Evaluation Program, 9609 Medical Center Drive, Bethesda, MD 20892, USA.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.affiliation: NCIC Clinical Trials Group, Queen's University Kingston, Ontario K7L 3N6, Canada.
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.affiliation: Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON 5MG 2M9, Canada.
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Drug Development Unit, Royal Marsden Hospital/The Institute of Cancer Research, Downs Rd, Sutton, Surrey SM2 5P, United Kingdom.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Doctor Molewaterplein 50-60, Rotterdam, Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.affiliation: Gustave Roussy Cancer Campus, DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), 114 rue Edouard Vaillant, 94800 Villejuif, France; Université Paris-Sud XI, 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France. Electronic address: Jean-charles.soria@gustaveroussy.fr.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents
keywords: Dose limiting toxicity; Maximum tolerated dose; Phase 1; Recommended phase 2 dose; Targeted agents; Toxicities; Trial design