OXFORD PRECISION ONCOLOGY FOR SARCOMA (OX-POS); PROSPECTIVE, LONGITUDINAL, OBSERVATIONAL STUDY WITH INTEGRATION OF NAVIFY® PATHWAY DECISION SUPPORT (OXPOS)

Research summary

The research methodology is based on a single centre observational cohort study,with an internal blinded comparison where each patient acts as their own control. The study is based on the premise of achieving high dimensional prospective data collection in a sufficient number of patients to allow for credible and comprehensive evaluation of the scope of the precision approach and its cost-effectiveness in a specified context of rare cancers. The participants are managed entirely by the standard of care pathway,but consents are obtained for study interventions and data analysis. Specifically,this includes for excess diagnostic tissue for genomic analysis and electronic data to be collected and then integrated in the protocol using the methodology outlined below. The other extra procedures for the patient are potentially a further blood test and CT or ultrasound radiologically guided tumour biopsy procedure,and patient reported questionnaires on quality of life and assessing the impact of a precision oncology consultation. The impact on the staff participants are questionnaires testing cognitive decision making aspects of complex OxPOS data. 1. Scope: A single UK comprehensive sarcoma centre,prospective observation study of precision oncology compared to standard of care. 2. Target population: adults,age over 18,unselected but able to sign informed consent,consecutive patients with diagnosis confirmed as high-grade sarcoma by the Oxford sarcoma MDT. 3. Duration: Study over 4 years (48 months),to recruit 200-250 newly diagnosed patients with an event rate of approximately 20%,with longitudinal follow-up an average of 2-3 years per patient. The number of patients needed was based on a confidence level of 95% that the real level of events (changes from standard of care MDT decisions) following OxPOS-NAVIFY® is within ±5% of the high-grade sarcoma real-world population. The study design aims to be achievable. 1. The study primary endpoints are to firstly to establish the platform that will enable recruitment of 200-250 patients in two years,with a further two year follow up. Oxford manages 150-200 new patients per year with high-grade sarcoma of all subtypes. These numbers will allow us to rapidly recruit sufficient informative and consecutive ‘all comer’ patients. 2. The strategy is focused on a dedicated team committed to project delivery in order that a direct comparison can be made between the standard of care MDT and the precision MDT,where there is consistency of membership,opinion that builds on existing in-house expertise. The within patient comparison is consistent and focuses on the platforms,aiming to eliminate bias wherever possible. In order to achieve the endpoints in terms of data,the data management approach focuses on a single clinical centre,one of the five comprehensive sarcoma centres in the UK. A multi-site protocol would add requirement for stratification between sites,dilution of the precision MDT impact and variation and inconsistency in terms of data acquisition/ EPR,genomic and imaging platforms. Once the OxPOS-NAVIFY® platform is established however,the issue of diverse EPR and MDT platforms in different sites may be addressed to facilitate the use of the platform across the UK and elsewhere in future collaborative study and networks,using the Cloud (remote data storage) based functionality of the platform. 3. The primary endpoint is a performance comparison between the utility of the data integrated by the OxPOS-NAVIFY® system with that of standard of care. As OxPOS-NAVIFY® is the enabling technology,the platform’s value is integrated with the disruptive technologies of functional and quantitative imaging,with FoundationOne® (Heme-SARC) genomic testing,methylome arrays and other tests,single cell and DNA/RNA technologies that provide more cutting edge analysis. 4. The secondary endpoints are focused on questions that the analytical and integrated data should be able to address,as well as the MDT process and decision making. Data from various sources (e.g.,electronic patient record collected via Cerner-Millennium,genomic data,DNA and RNA sequencing etc.) will first flow into a clinical data warehouse (OUH Clinical Data Warehouse for data storage),and then data are pseudonymised before feeding into NAVIFY® digital platform. The main objectives will be delivered by the following work-packages components of the study design,each with attributable personal. 1. Evaluation of the commercial NAVIFY® digital integration platform and Nexus® based support tools within the sarcoma precision oncology context: The aim is to first establish and to then integrate the NAVIFY® platform with the OUHFT electronic patient record system provided by Cerner-Millennium. This will be achieved in two stages,the first to ensure interoperability (connectivity) of EPR,Aria and Orbit data with frequent,but not real-time downloads,that are integrated in the OUHFT-Oxford clinical data warehouse. Here,pseudonymised data can be collected from primary clinical data sources and provided for integration into the platform of NAVIFY®. In time,the aim is to establish the integration in real-time to facilitate integration of standard of care data with new data analysis from genomics and imaging (see below). The utilities package from NAVIFY® oncology will support Sarcoma guidelines,more bespoke sarcoma subtype guidelines,Clinical trial search engines,identification of driver variants through FoundationOne® integration and ultimately to comparative databases of real-world clinical outcome data. The Roche team consisting healthcare consultants and/or implementation managers will assist by conducting workflow mapping and analysis e.g.,reduced steps of completing a certain task,decreased time needed from users and switches between users and systems,reduced variations between patient care pathways,standardised workflows and procedures of data collection/integration. Moreover,we will evaluate whether and how NAVIFY® improves the clinical trial recruitment (e.g.,supporting clinicians in identifying suitable trials,increasing the number of trials identified for a patient,and enabling clinicians to find trials of higher relevance faster; number of patients matched to the clinical trials will be tracked and compared to reported numbers in literature),and how NCCN/ ESMO clinical guidelines applications and/or digitalised local guidelines improves the efficiency and communications with the care team,reduces the administrative burden,and enables the documentation of reasons of deviating from the guideline recommendations. 2. Comprehensive range of somatic genomic investigations: The aim is to utilise a validated genomic targeted panel based on DNA and RNA,in this case FoundationOne Heme (Sarcoma panel) the FM-test,with additional RNASeq and whole exome sequencing when required. Here we will identify common variants (changes in DNA and RNA) in all the tumour samples with a unified platform. The FM-test performed in external service facilities is based on an ISO accredited cancer genome analysis offering reliability,reproducibility and quality control. Importantly for sarcoma,sample collection will extend to multiple tumour cores obtained after diagnostic sampling or in the surgical theatre (surplus to diagnostic requirements) using an existing standard operating procedure for this post resection tissue collection process. The additional added value will be epigenome arrays,transcriptome with RNA sequencing,and new single cell technologies now adapted for the clinic. Identification of targets and agents,will also seed discovery projects investigating sensitivity and resistance molecular mechanisms to agents using patient data. 3. Development of pathways for the evaluation of germline findings for sarcoma: By integrating OxPOS with the NHSE opportunities through the NHS Genomic Medicine Service Alliance,we will utilise an extended sarcoma specific germline candidate gene list (~30 genes) for a targeted candidate gene approach for germline susceptibility. Here we will report the frequency of these variants,report on the actions as a result of their identification,such as the secondary screening,risks of radiation induced second cancers,chemotherapy toxicity,response to targeted treatments and follow up. All germline findings will follow the American College of Medical Genomic and Genetics,ACMG) duty of care list. 4. Sarcoma heterogeneity and growth rate assessed by PET-CT and MRI: We will uniquely collate longitudinal wholebody imaging data using functional PET-CT and contrast enhanced MRI. The aim is to automate segmentation in 3 dimensions of index lesions,and to quantify the volumes of lesions and dimensions over time. By comparing scans performed at regular intervals,the relative growth rate can be calculated per tumour (volume/diameter per week),and compare the rate of change before and after introduction of a treatment. The diversity in the textures or signals from FDG uptake within each tumour,and the distribution in the volume can be quantified by use of a heterogeneity index,and the rate of change also quantified with time. Defining the functional heterogeneity in this way advances the deeper interrogation of PET CT and MRI in sarcoma,and is especially powerful as a radiomics initiative where genomics and imaging data are analysed together. Automating such processing is an advance that is relevant to other cancers and can be better interpreted when compared to the spatial distribution of genomic variants in a given tumour. 5. Cognitive analysis of decision making in the MDT: The underlying hypothesis is that OxPOS-NAVIFY® allows consideration of more thorough inputs,more structured evaluation of available data,resolving uncertainty earlier,facilitating checks of the guidelines,supporting better group communication and alignment in reproducible decisionmaking etc. For this to be fully evaluated,longitudinal assessments of clinician decision making are envisaged. There are a few design options to evaluate the impacts on cognitive burden and decision-making confidence as initial assessments. From a study design perspective,a comparative design is the most appropriate. Here,cognitive burden and agility are measured after the standard of care MDT,and also after OxPOS-NAVIFY® supported precision MDT early in the pathway. Several areas of specific measurement can be easily undertaken using multi-scale assessments. For example,for cognitive burden,NASA Task load index is a validated six question scale,and for measuring decision making confidence,a self-reporting questionnaire based on POMS be utilised,and a semistructured interview performed with specific questions. 6. Health economic evaluation of the OxPOS cohort: There is a lack of prospective health-economic evaluation of precision oncology. Determination of salaries,costs of testing and capital resources will be calculated based on standard national UK rate and NHS scales,with assumptions including an extended skill set (higher cost) in the precision MDT compared to a standard of care MDT. These are relatively straightforward approaches that may offer patient specific valuations as well as the cohort as a whole. Deeper modelling techniques are going to be critical,as patient specific heterogeneity across the longitudinal patient pathway would be the only way to fully offset the investments early on in the way with any eventual longer-term benefit overall.

Principal Investigator

Prof Bass Hassan

Contact us

Email: latephaseoncology@ouh.nhs.uk

IRAS number

299632