Alternative phase I dose escalation study designs: CRM, BLRM, mTPI, and PGDE

The "3 + 3 design" is the most commonly used design in phase I dose escalation study and over 95% of phase I clinical trials in oncology use the "3 + 3 design". However, in some situations, the "3 + 3 design" may not be the best choice for finding the maximum tolerable dose (MTD) and alternative dose escalation study designs are necessary.

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)

where CRM, modified CRM, and BLRM are model based method and mTPI is a mixture of both rule-based and model based method. 

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 

mTPI is Bayesian like CRM and BLRM, but rule-based like the "3 + 3 design". The method is proposed by Yuan Ji et al in their paper "a modified toxicity probability interval method for dose-finding trials". The method can be implemented by excel add-on or R scripts (download for free).

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.

Phase I Clinical Trial Design by Drs. Rubinstein and Simon discussed additional study designs for phase I dose escalation studies in addition to the "3 + 3 design", original CRM, and amendments and alteration of CRMs:

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.

Further readings:

• Phase 1 Trial Design: Is 3 + 3 the Best?
• Dose Escalation Methods in Phase I Cancer Clinical Trials
• Bayesian Continual Reassessment Method Designs for Phase I Dose-Finding Trials
• Phase I dose‑escalation study of the HSP90 inhibitor AUY922 in Japanese patients with advanced solid tumors
• Phase I Dose-Escalation Study of LCL161, an Oral Inhibitor of Apoptosis Proteins Inhibitor, in Patients With Advanced Solid Tumors