Abstract #302014

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JSM 2003 Abstract #302014
Activity Number: 219
Type: Contributed
Date/Time: Tuesday, August 5, 2003 : 9:00 AM to 10:50 AM
Sponsor: Biopharmaceutical Section
Abstract - #302014
Title: Simon's 4B Accelerated Titration Design: Simulations of Toxicity-Dependent Patient Withdrawal
Author(s): Paul Henry Frankel*+ and Christopher Ruel
Companies: City of Hope and City of Hope
Address: 1500 East Duarte Rd., Duarte, CA, 91010-3012,
Keywords: accelerated ; titration ; simulation ; Phase I ; censoring
Abstract:

Simon's 4B accelerated titration design (1997) for first in human use dose-finding clinical trials allows for an initial phase of rapid dose increases and intrapatient dose escalation, with simple rules for reducing the increments of the dose escalation based on observed toxicities. In this manner few cycles are treated at an ineffective dose, and all patients, providing they continue to get further cycles, will receive a potentially therapeutic dose. By reverting to a more conservative escalation upon moderate toxicities, few patients are expected to be treated above the MTD. In the analysis of the resulting clinical trial data, a model for the DLT rate is used that accounts for patient variability, the dose, and the cumulative dose. These characteristics make the 4B design appealing and we have implemented this design in a Phase I study of a novel microtubule inhibitor. One concern, however, is the role of early patient withdrawal and differing number of courses given to patients that may be related to toxicity. Such censoring can alter the estimates of the MTD, and we present a variety of simulations demonstrating the possible effects.

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