Dose-finding designs using a novel quasi-continuous endpoint for multiple toxicities

Autor: Monia Ezzalfani, Sarah Zohar, Rui Qin, Marie-Cécile Le Deley, Sumithra J. Mandrekar
Rok vydání: 2011
Předmět:
Statistics and Probability
Maximum Tolerated Dose
Epidemiology
dose-finding design
isotonic regression
Context (language use)
Antineoplastic Agents
Logistic regression
01 natural sciences
Continual reassessment method
010104 statistics & probability
03 medical and health sciences
0302 clinical medicine
Frequentist inference
Statistics
Isotonic regression
Medicine
Humans
Computer Simulation
multiple toxicity score
0101 mathematics
Research Articles
Likelihood Functions
Models
Statistical
Clinical Trials
Phase I as Topic
Dose-Response Relationship
Drug
business.industry
Nonparametric statistics
phase I
molecularly targeted agents
3. Good health
Sample size determination
030220 oncology & carcinogenesis
Sample Size
Toxicity
oncology
business
continual reassessment method
quasi-continuous endpoint
Zdroj: Statistics in Medicine
Statistics in Medicine; Vol 32
ISSN: 1097-0258
Popis: The aim of a phase I oncology trial is to identify a dose with an acceptable safety profile. Most phase I designs use the dose-limiting toxicity, a binary endpoint, to assess the unacceptable level of toxicity. The dose-limiting toxicity might be incomplete for investigating molecularly targeted therapies as much useful toxicity information is discarded. In this work, we propose a quasi-continuous toxicity score, the total toxicity profile (TTP), to measure quantitatively and comprehensively the overall severity of multiple toxicities. We define the TTP as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each grade and toxicity type. We propose a dose-finding design, the quasi-likelihood continual reassessment method (CRM), incorporating the TTP score into the CRM, with a logistic model for the dose–toxicity relationship in a frequentist framework. Using simulations, we compared our design with three existing designs for quasi-continuous toxicity score (the Bayesian quasi-CRM with an empiric model and two nonparametric designs), all using the TTP score, under eight different scenarios. All designs using the TTP score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the quasi-likelihood CRM ranged from 80% to 90%, with similar results for the quasi-CRM design. These designs with TTP score present an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents.
Databáze: OpenAIRE
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