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

• Published in: European journal of cancer (1990) 2014-08, Vol.50 (12), p.2040-2049
• Main Authors: Postel-Vinay, Sophie, Collette, Laurence, Paoletti, Xavier, Rizzo, Elisa, Massard, Christophe, Olmos, David, Fowst, Camilla, Levy, Bernard, Mancini, Pierre, Lacombe, Denis, Ivy, Percy, Seymour, Lesley, Le Tourneau, Christophe, Siu, Lillian L, Kaye, Stan B, Verweij, Jaap, Soria, Jean-Charles
• Format: Article
• Language: English
• Subjects: Adult; Antineoplastic Agents - toxicity; Biological and medical sciences; Clinical Trials, Phase I as Topic; Dose limiting toxicity; Dose-Response Relationship, Drug; Europe; Female; Hematology, Oncology and Palliative Medicine; Humans; Male; Maximum tolerated dose; Medical sciences; Molecular Targeted Therapy - methods; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Pharmacology. Drug treatments; Phase 1; Recommended phase 2 dose; Research Design; Retrospective Studies; Targeted agents; Toxicities; Trial design; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2014.04.031

Abstract Introduction 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. Patients and 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