Escalation with overdose control is more efficient and safer than accelerated titration for dose finding

André Rogatko, Galen Cook-Wiens, Mourad Tighiouart, Steven Piantadosi

Research output: Contribution to journalArticle

Abstract

The standard 3 + 3 or "modified Fibonacci" up-and-down (MF-UD) method of dose escalation is by far the most used design in dose-finding cancer trials. However, MF-UD has always shown inferior performance when compared with its competitors regarding number of patients treated at optimal doses. A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. In June 2012, the U S Food and Drug Administration (FDA) rejected the proposal to use Escalation with Overdose Control (EWOC), an established dose-finding method which has been extensively used in FDA-approved first in human trials and imposed a variation of the MF-UD, known as accelerated titration (AT) design. This event motivated us to perform an extensive simulation study comparing the operating characteristics of AT and EWOC. We show that the AT design has poor operating characteristics relative to three versions of EWOC under several practical scenarios. From the clinical investigator's perspective, lower bias and mean square error make EWOC designs preferable than AT designs without compromising safety. From a patient's perspective, uniformly higher proportion of patients receiving doses within an optimal range of the true MTD makes EWOC designs preferable than AT designs.

Original languageEnglish (US)
Pages (from-to)5288-5303
Number of pages16
JournalEntropy
Volume17
Issue number8
DOIs
StatePublished - 2015
Externally publishedYes

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titration
dosage
proposals
safety
proportion
cancer
simulation

Keywords

  • Accelerated titration
  • Cancer early trials
  • Dose finding
  • Escalation with overdose control
  • EWOC
  • Phase I trials

ASJC Scopus subject areas

  • Physics and Astronomy(all)

Cite this

Escalation with overdose control is more efficient and safer than accelerated titration for dose finding. / Rogatko, André; Cook-Wiens, Galen; Tighiouart, Mourad; Piantadosi, Steven.

In: Entropy, Vol. 17, No. 8, 2015, p. 5288-5303.

Research output: Contribution to journalArticle

Rogatko, A, Cook-Wiens, G, Tighiouart, M & Piantadosi, S 2015, 'Escalation with overdose control is more efficient and safer than accelerated titration for dose finding', Entropy, vol. 17, no. 8, pp. 5288-5303. https://doi.org/10.3390/e17085288
Rogatko, André ; Cook-Wiens, Galen ; Tighiouart, Mourad ; Piantadosi, Steven. / Escalation with overdose control is more efficient and safer than accelerated titration for dose finding. In: Entropy. 2015 ; Vol. 17, No. 8. pp. 5288-5303.
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