Dose-finding designs for trials of molecularly targeted agents and immunotherapies

J Biopharm Stat. 2017;27(3):477-494. doi: 10.1080/10543406.2017.1289952. Epub 2017 Feb 6.


Recently, there has been a surge of early phase trials of molecularly targeted agents (MTAs) and immunotherapies. These new therapies have different toxicity profiles compared to cytotoxic therapies. MTAs can benefit from new trial designs that allow inclusion of low-grade toxicities, late-onset toxicities, addition of an efficacy endpoint, and flexibility in the specification of a target toxicity probability. To study the degree of adoption of these methods, we conducted a Web of Science search of articles published between 2008 and 2014 that describe phase 1 oncology trials. Trials were categorized based on the dose-finding design used and the type of drug studied. Out of 1,712 dose-finding trials that met our criteria, 1,591 (92.9%) utilized a rule-based design, and 92 (5.4%; range 2.3% in 2009 to 9.7% in 2014) utilized a model-based or novel design. Over half of the trials tested an MTA or immunotherapy. Among the MTA and immunotherapy trials, 5.8% used model-based methods, compared to 3.9% and 8.3% of the chemotherapy or radiotherapy trials, respectively. While the percentage of trials using novel dose-finding designs has tripled since 2007, the adoption of these designs continues to remain low.

Keywords: Dose-finding methods; immunotherapy; maximum tolerated dose; optimal dose; phase 1 designs; targeted therapy.

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Clinical Trials, Phase I as Topic*
  • Dose-Response Relationship, Drug
  • Humans
  • Immunotherapy*
  • Maximum Tolerated Dose
  • Medical Oncology
  • Molecular Targeted Therapy*
  • Neoplasms / drug therapy


  • Antineoplastic Agents