title: Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.
abstract: OBJECTIVE
  The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose.
  
  
  METHODS
  We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib.
  
  
  RESULTS
  A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%.
  
  
  CONCLUSIONS
  When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials.
authors.affiliation: Shing M. Lee, Daniel Backenroth, Ying Kuen Ken Cheung, and Dawn L. Hershman, Columbia University, New York, NY; Diana Vulih and Barry Anderson, Theradex Systems, Princeton, NJ; and Percy Ivy and Lori Minasian, National Cancer Institute, Bethesda, MD. sml2114@columbia.edu.
authors.forename: Shing M
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Shing M. Lee, Daniel Backenroth, Ying Kuen Ken Cheung, and Dawn L. Hershman, Columbia University, New York, NY; Diana Vulih and Barry Anderson, Theradex Systems, Princeton, NJ; and Percy Ivy and Lori Minasian, National Cancer Institute, Bethesda, MD.
authors.forename: Daniel
authors.initials: D
authors.lastname: Backenroth
authors.affiliation: Shing M. Lee, Daniel Backenroth, Ying Kuen Ken Cheung, and Dawn L. Hershman, Columbia University, New York, NY; Diana Vulih and Barry Anderson, Theradex Systems, Princeton, NJ; and Percy Ivy and Lori Minasian, National Cancer Institute, Bethesda, MD.
authors.forename: Ying Kuen Ken
authors.initials: YK
authors.lastname: Cheung
authors.affiliation: Shing M. Lee, Daniel Backenroth, Ying Kuen Ken Cheung, and Dawn L. Hershman, Columbia University, New York, NY; Diana Vulih and Barry Anderson, Theradex Systems, Princeton, NJ; and Percy Ivy and Lori Minasian, National Cancer Institute, Bethesda, MD.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Hershman
authors.affiliation: Shing M. Lee, Daniel Backenroth, Ying Kuen Ken Cheung, and Dawn L. Hershman, Columbia University, New York, NY; Diana Vulih and Barry Anderson, Theradex Systems, Princeton, NJ; and Percy Ivy and Lori Minasian, National Cancer Institute, Bethesda, MD.
authors.forename: Diana
authors.initials: D
authors.lastname: Vulih
authors.affiliation: Shing M. Lee, Daniel Backenroth, Ying Kuen Ken Cheung, and Dawn L. Hershman, Columbia University, New York, NY; Diana Vulih and Barry Anderson, Theradex Systems, Princeton, NJ; and Percy Ivy and Lori Minasian, National Cancer Institute, Bethesda, MD.
authors.forename: Barry
authors.initials: B
authors.lastname: Anderson
authors.affiliation: Shing M. Lee, Daniel Backenroth, Ying Kuen Ken Cheung, and Dawn L. Hershman, Columbia University, New York, NY; Diana Vulih and Barry Anderson, Theradex Systems, Princeton, NJ; and Percy Ivy and Lori Minasian, National Cancer Institute, Bethesda, MD.
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.affiliation: Shing M. Lee, Daniel Backenroth, Ying Kuen Ken Cheung, and Dawn L. Hershman, Columbia University, New York, NY; Diana Vulih and Barry Anderson, Theradex Systems, Princeton, NJ; and Percy Ivy and Lori Minasian, National Cancer Institute, Bethesda, MD.
authors.forename: Lori
authors.initials: L
authors.lastname: Minasian
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib / Q000008:administration & dosage* / Q000009:adverse effects; D002986:Clinical Trials as Topic / Q000379:methods*; D018572:Disease-Free Survival; D054796:Drug Dosage Calculations; D006801:Humans; D053208:Kaplan-Meier Estimate; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016016:Proportional Hazards Models; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D012107:Research Design; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D000069286:Bortezomib