Cytel's EAST software version 6.3 introduced a new module 'ESCALATE' which includes additional phase I dose escalation study designs. In additional to the standard "3 + 3 design", it contains the following designs:
- CRM (Continual Reassessment Method)
- Modified CRM
- BLRM (Bayesian Logistic Regression Method)
- mTPI (Modified Toxicity Probability Interval Design)
The original CRM is a Bayesian model-based method and uses all available information from doses to guide assignment of the next dose cohort. A CRM simulator can be downloaded from MD Anderson biostatistics website. The modified CRM makes the CRM more like the "3 + 3 design" (can start at lowest dose, allow multiple patients per cohort, do not allow skipping when escalating) for acceptability. A CRM and modified CRM program developed by Dr Steven Piantados can be downloaded from his website. BLRM is commonly used with overdose control (so called EWOC - Escalation With Overdose Control). In this method, models begin with initial estimates of knowledge based on prior clinical data or pre-clinical data. Models are then updated with new information as it becomes available. Updated information forms the basis of dose escalation recommendations. The principles of Bayesian Logistic regression models are:
- precision of model estimates incorporated into dosing decisions
- restriction of the chance of exposing patients to excessive toxicity, whilst allowing clinicians to make informed dosing decisions based on estimated probabilities of under-dosing and targeted-dosing
These methods and their usage with EAST ESCALATE module were explained in a free online Webinar "New module for Phase 1 dose escalation study design". ESCALATE module in EAST can perform simulation and interim monitoring for each of these methods.
Accelerated titration designs which are characterized by (i) A rapid initial escalation phase; (ii) Intra-patient dose escalation; and (iii) Analysis of results using a model that incorporates parameters for intra-patient variation in toxic effects, cumulative toxicity and steepness of dose-toxicity effects. The analytic model incorporates data from all courses of therapy and for graded toxicity levels.
Pharmacokinetically Guided Dose Escalation (PGDE) which is based on the mouse and human AUC to escalate to an MTD by targeting a maximal tolerated AUC. The efficiency of PGDE relies on the assumption that drug toxicity is really a function of drug AUC, and that equivalent AUC for human and mouse will result in equivalent toxicity.
- Phase 1 Trial Design: Is 3 + 3 the Best?
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- Phase I Dose-Escalation Study of LCL161, an Oral Inhibitor of Apoptosis Proteins Inhibitor, in Patients With Advanced Solid Tumors