CRUKD/21/004 : DETERMINE (aDvancing gEnomically maTchEd tReatMents IN rare cancErs)

Background: The increased uptake of Next Generation Sequencing in the clinic presents an opportunity to identify genomic alterations in adult cancers, paediatric and teenage young adult (TYA) populations at a scale that has not been previously achievable.

Targetable alterations are identifiable across a range of tumour types where there may be established and effective drugs available but licensed in a different indication. Often these agents are untested in rare populations due to previous challenges in identifying patients.

Recent learnings from the National Lung Matrix study show that genomic complexity and transcriptional context of tumours are highly relevant in determining response to a targeted therapy.

The increased availability of genetic testing and potential to explore molecular contexts presents a timely opportunity to explore new indications for existing drugs in rare cancers.

Aims: The overall aim of DETERMINE is to evaluate the efficacy of targeted therapies outwith licensed indication in rare adult cancers, paediatric and TYA tumours with actionable genomic alterations and to identify genomic and immune contextual influences on response to therapy.

Methods: DETERMINE is a first of its kind basket-umbrella platform trial in the UK to establish a structured joint adult/paediatric framework for collection of robust clinical outcome data linked with a transformative translational research program.

Patients must have pre-identified molecular alterations either through NHS England new national Genomic Medicine Service or participation in another molecular screening program prior to enrolment in DETERMINE. Patients will be allocated to a matched treatment (if available) according to molecular alteration.

A Bayesian design will be used to identify efficacy signals on small numbers of patients, accounting for differences in histology, age and genomic complexity.

Cohorts meeting pre-defined ‘go’ criteria will trigger a selected expansion to further explore efficacy in specific sub-groups of patients.

Primary endpoint is durable clinical benefit (DCB) with secondary endpoints of ORR, time to treatment discontinuation, PFS, OS and exploratory translational analyses. Fresh tumour tissue will be acquired at baseline for whole genome and RNA sequencing. Blood samples will be collected for ctDNA analysis every 6 weeks.

How the results of this research will be used: Data generated will be used to support application to the cancer drugs fund for rare tumours and implementation into the NHS for indications with promising clinical efficacy.

New insights into contextual response to targeted therapies will lead to enhanced biomarker selection for those most likely to respond