title: Dose Finding of Small-Molecule Oncology Drugs: Optimization throughout the Development Life Cycle.
abstract: In the current era of rapid marketing approval for promising new products in oncology, dose finding and optimization for small-molecule oncology drugs occurs throughout the development cycle and into the postmarketing setting. Many trials that support a regulatory application have high rates of dose reductions and discontinuations, which may result in postmarketing requirements (PMR) to study alternate doses or dosing schedules. Kinase inhibitors particularly have been susceptible to this problem, and among the 31 approved drugs of this class, the approvals of eight have included such PMRs and/or commitments. Thus, the current paradigm for dose finding and optimization could be improved. Newer strategies for dose finding rather than traditional 3 + 3 designs should be considered where feasible, and dose optimization should be continued after phase I and throughout development. Such strategies will increase the likelihood of a right dose for the right drug at the time of regulatory approval. Clin Cancer Res; 22(11); 2613-7. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "NEW APPROACHES FOR OPTIMIZING DOSING OF ANTICANCER AGENTS".
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: U.S. Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Kim
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: U.S. Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Rajeshwari
authors.initials: R
authors.lastname: Sridhara
authors.affiliation: U.S. Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
authors.affiliation: U.S. Food and Drug Administration, Silver Spring, Maryland. amy.mckee@fda.hhs.gov.
authors.forename: Amy E
authors.initials: AE
authors.lastname: McKee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors