Seamless phase I/II adaptive designs for precision medicine trials


   MRC Biostatistics Unit

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  Dr Haiyan Zheng  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The primary objective of phase I clinical trials is to estimate the maximum tolerated dose, the highest dose level that maintains the risk of toxicity below a target level. Promising doses are selected for evaluating the early efficacy in a subsequent phase II trial. Seamless phase I/II designs, integrating the evaluation of toxicity and efficacy, are an efficient approach that can expedite the drug development [1]. Such designs have gained increasing attention in the development of immunotherapies and molecularly targeted agents, which have now been established as a fundamental hallmark of precision medicine [2]. In contrast to conventional cytotoxic agents, the objective thus becomes to determine the minimally biologically active (sometimes also called the minimum effective) dose that is associated with an acceptable level of toxicity and promising efficacy. Furthermore, this optimal dose may differ according to the patient’s individual characteristics, e.g., their treatment history. To increase the patient’s chance to benefit, drug combinations are often of emerging interest. Designing efficient phase I/II trials for drug combinations is nonetheless challenging [3].  

This project will develop novel seamless adaptive designs for early phase dose-finding trials. To start with, design and analysis of phase I-II trials with a single agent will be considered. Methods to be developed will allow for i) the use of both toxicity and efficacy data collected per patient to inform timely dose recommendations, ii) joint analysis of various patient subgroups, defined by their biomarker information (e.g., measurements of characteristic biological properties or genetic aberration), and iii) borrowing of information from historical studies. The focus would later be shifted towards drug combination trials. Of particular interest is to propose flexible designs that permit addition of an experimental drug to the one under investigation in the ongoing trial, whilst maintaining the desired operating characteristics.

The project will be undertaken under the joint supervision of Dr Haiyan Zheng and Dr Pavel Mozgunov. The student will be based in the MRC Biostatistics Unit (BSU), University of Cambridge. Founded in 1913, the BSU is one of the largest group of biostatisticians in Europe, and a major centre for research, training and knowledge transfer. The group, and the supervisors particularly, have a long-standing relationship with clinical trial units in the UK and pharmaceutical companies around the world that will benefit the student and will allow them to build their own collaboration network.

The supervisors:

·       Dr Haiyan Zheng, CRUK Research Fellow in Statistical Methodology, has expertise in developing Bayesian methods, especially for informative prior specification and robust inference, into modern clinical trials.

·       Dr Pavel Mozgunov, Programme Leader Track and NIHR Advanced Research Fellow in Medical Statistics, has extensive experience in methodological development of adaptive designs for, and the implementation in, early phase clinical trials.

This project will also benefit from the collaboration with Prof Xavier Paoletti (Institut Curie Paris, France), a leading expert in developing advanced dose-finding designs for early phase trials and their implementation in clinical practice. The collaboration with Prof Paoletti who is involved in both development and practical application of innovative design will enhance the real-world utility for early phase clinical trials. Intramural travel grants will be sought to support research visits to Prof Paoletti at the Institut Curie Paris during the studentship.

The student will also benefit from the PPI work done within both Dr Zheng’s and Dr Mozgunov’s fellowship programmes and will seek the contribution on the direction of the project from the patient representatives that the supervisors are working with.

HOW TO APPLY

You are applying for a PhD studentship from the MRC TMRP DTP. A list of potential projects and the application form is available online at:

http://www.methodologyhubs.mrc.ac.uk/about/tmrp-doctoral-training-partnership/

Please complete the form fully. Incomplete forms will not be considered. CVs will not be accepted for this scheme.

Please apply giving details for your first choice project. You can provide details of up to two other TMRP DTP projects you may be interested in at section B of the application form.

Before making an application, applicants should contact the project supervisor to find out more about the project and to discuss their interests in the research before 09 January 2023.

The deadline for applications is 4pm (GMT) 16 January 2023. Late applications will not be considered.

Completed application forms must be returned to: [Email Address Removed]

Informal enquiries may be made to Dr Haiyan Zheng - [Email Address Removed]

Mathematics (25)

Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

[1] Hobbs BP, Barata PC, Kanjanapan Y, et al. Seamless Designs: Current Practice and Considerations for Early-Phase Drug Development in Oncology. J Natl Cancer Inst. 2019; 111:118-128.
[2] Schork N. Personalized medicine: Time for one-person trials. Nature 2015; 520:609–611.
[3] Wages NA, Slingluff CL Jr, Petroni GR. Statistical controversies in clinical research: early-phase adaptive design for combination immunotherapies. Ann Oncol. 2017; 28:696-701