title: Dose-response relationship in phase i clinical trials: a European Drug Development Network (EDDN) Collaboration Study.
abstract: BACKGROUND
  Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.
  
  
  METHODS
  We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.
  
  
  RESULTS
  Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%-80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).
  
  
  CONCLUSIONS
  Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%-80% of MTD).
authors.affiliation: The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. The Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno García
authors.affiliation: The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. The Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.affiliation: Drug Development Department (DITEP) Gustave Roussy, Villejuif, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gomez-Roca
authors.affiliation: The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. The Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Cassier
authors.affiliation: Research Unit for Molecular Therapy of Cancer, Vall d' Hebron University Hospital, Vall d' Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Morales-Barrera
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Del Conte
authors.affiliation: Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gallerani
authors.affiliation: The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
authors.forename: Andre T
authors.initials: AT
authors.lastname: Brunetto
authors.affiliation: Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.affiliation: Southern Europe New Drug Organization (SENDO) Foundation, Milan, Italy. Istituto di Candiolo, and Fondazione del Piemonte per l'Oncologia IRCCS, Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Centre Oscar Lambret, Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Penel
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Emile
authors.initials: E
authors.lastname: Voest
authors.affiliation: University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Evans
authors.affiliation: Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Wilson
authors.affiliation: Drug Development Department (DITEP) Gustave Roussy, Villejuif, France.
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Research Unit for Molecular Therapy of Cancer, Vall d' Hebron University Hospital, Vall d' Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.affiliation: The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. The Institute of Cancer Research, Sutton, United Kingdom. stan.kaye@rmh.nhs.uk.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D017321:Clinical Trials, Phase I as Topic; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents