About MUCE

In modern early-phase clinical trials, often times multiple doses of a new drug are tested in multiple indications to identify the promising doses and arms for phase II or phase III trials. Traditionally, each dose or indication is tested separately in a single trial, resulting in multiple protocols and multiple trials.

MUCE is a new Bayesian solution for cohort expansion trials or master protocol trials, in which multiple dose(s) and multiple indication(s) are expanded in parallel. It's built on Bayesian hierarchical models with multiplicity control (BHM-MC) to adaptively borrow information across patient groups to achieve three major goals:

1. Increase the power (probability of selecting a promising drug for further development) for drug development
2. Reduce sample size
3. Control the type I error rate (probability of selecting an unpromising drug for further development)

MUCE Solution

As a comprehensive statistical solution, MUCE can be used to calculate the sample size or power, and to conduct interim and final data analyses for making critical decisions.

For sample size/power calculation, MUCE requires inputs of type I error, power/sample size, reference rate (historical control rate) and target rate for each arm. For data analysis, MUCE requires inputs of reference rate, number of responders and patients enrolled at the time of interim analysis or final analysis.

These can be applied in any clinical trials with 2 or more arms, including:

• Phase 1b trials with multiple expansion cohorts
• Phase 2 trials with multiple arms
• Master protocols including basket, umbrella, and platform trials

MUCE Benefits

Compared to the Simon’s two-stage design and existing other designs for multiple expansion cohort trials (eg. Berry’s BHM [1], etc.), MUCE could control the family-wised type 1 error rate and maintain power with a smaller sample size.

MUCE Consulting Service

We offer MUCE consulting servcie that spans the entire trial process

Some of recent examples of MUCE consulting services

1. In 2018, MUCE is applied to a Chinese Phase 1a-1b Seamless trial in which up to three doses and four indications will be expanded. This means the trial can expand as many as 12 arms in parallel. The IND application has been approved and trial started with a first patient enrolled. MUCE turns out to be the only design that can manage 12 arms with limited sample size.
2. In 2019, MUCE is applied to a US Phase 1a/1b trial to help design the multiple expansion cohorts. The trial has three cohorts to expand after the dose escalation stage, to determine if the RP2D can exhibit anti-tumor activities in three different indications. The trial is submitted for IND approval in US.
3. In 2019, MUCE is applied to a three-arm phase II trial in which each arm investigates the efficacy of the combination of two immune therapies in three lines of cancer treatments. The sample size of trial is cut into half compared to Simon’s two-stage design.
4. In 2019, MUCE is applied to a two-arm phase 1b/II trial, in which MUCE is used to guide a two-arm expansion cohort design and go/no-go decision for each arm. MUCE is compared to the Bayesian method in Berry et al. (2013) and shows much improved control of type I error rate.

A proposal to transform phase 1 oncology trials at company xyz
Laiya Consulting, Inc.
September 28, 2019

Purpose:

to promote the use of a novel phase 1 trial design suite that tailors to modern needs of phase 1 clinical trials in oncology.

Introduction:

Based on a set of innovative statistical designs and approaches, Laiya proposes a suite of solutions to transform phase 1 trials for new drug development (Figure 1). The solutions aim to short the trial duration, reduce sample size and cost, but still maintain safety and sufficient power. Innovatively, we also provide decision tools that help control the type I error of critical decision making to reduce the failure rates of phase 2 and 3 trials.

Figure 1: Laiya One -- A 21st Century Phase 1 Trial Design Suit

How/Where can Laiya-One Help During Phase 1 Development

Laiya-One provides end-to-end services on the entire phase 1 trial and drug develop (Figure 2)

Figure 2 Laiya-One main functions for the phase 1 trial and drug development

Available Designs and Benefits:

The suite includes four novel designs.

1. The i3+3 design (and extensions). It is a cohort-based dose-finding design suitable for standard DLT-based phase 1a trials. Below are some notable features and benefits.
   • i3+3 has much higher chance of identifying the true MTD
   • i3+3 has proven success at US and Chinese IND applications
   • i3+3 is operationally as simple as the 3+3 design
   • i3+3 variations (mi3+3 and ci3+3) allows biomarker subgroups and combo dose finding
2. The PoD-TPI design. It is a break-through type of design allowing faster patient enrollment for standard DLT-based phase 1a trials. Below are some notable features and benefits. It is the first type of dose-finding designs that offers the following features and benefits.
   • PoD-TPI quantifies the risk of dose-finding decisions – this is critical if we want to speed up enrollment
   • PoD-TPI accelerates patient enrollment while maintaining safety
   • PoD-TPI assesses existing designs and their risks – important to benchmark future designs
3. The MUCE design. It is a novel design and decision-making tool allowing more efficient sample size/power/decision making process for phase 1b multiple expansion cohorts studies.
   • MUCE can accommodate multiple doses, schedules, combinations, and indications to be included in a single study.
   • MUCE results in a smaller sample size (as much as half) than the standard designs, such as the Simon’s two-stage design
   • MUCE has a build-in function to control the overall type I error rate – to reduce false selection of indication and dose for phase 2 trials

Examples:

The i3+3 design and its alternatives

1. Laiya has helped a US company to secure an IND approval including an mi3+3 design is used to help guide all comers and a biomarker-positive subpopulation go through dose finding states simultaneously. This greatly reduced the time and cost since without the mi3+3 design, two sequential dose-finding trials will be needed, one for the all comers and one for the subpopulation.
2. Laiya has helped multiple Chinese and US companies design seamless phase 1a dose-escalation and multiple expansion cohort trials. The dose-escalation part is based on the i3+3 design and the expansion cohort part is based on the MUCE design. This helps speed up the drug development with a single protocol, and the MUCE design results in 10-40% sample size reduction.
3. Laiya has helped with investigator initiated trials (IITs) in which the MUCE design is applied to multi-arm phase 2 basket trials. In a three-arm trial targeting different lines of therapy, the MUCE design results in a 50% sample size reduction when compared to the Simon’s two-stage design.