716TiP - DETERMINE: A pioneering UK precision medicine trial for rare cancers

Background

Precision medicine (PM) is transforming outcomes in cancer. Increasingly, through the nationwide uptake of genomic profiling, actionable alterations are identified in patients that could benefit from targeted therapies licensed in other indications. Rare cancers are under-represented in PM trials yet account for 22% of cancers overall and have limited treatment options. There is also a lack of translational research to understand differential outcomes in treatment response. Opportunity exists to fine-tune biomarker selection to repurpose existing therapies in rare cancer indications and identify novel therapeutic targets.

Trial design

DETERMINE (www.cruk.org/determine) is an innovative, multi-pharmaceutical open-label phase II ‘umbrella-basket’ platform trial developed with patient and public involvement. The study will evaluate the efficacy of licensed targeted medicines in unlicensed indications in rare adult, paediatric and teenage young adult cancers with actionable genomic alterations. All patients will undergo a mandatory baseline biopsy to facilitate a comprehensive translational research programme, evaluating the genomic, transcriptomic, and immune microenvironment of rare tumours. Main eligibility criteria include children and adults (age agnostic), diagnosed with an advanced cancer (tumour agnostic), actionable genomic alteration (identified through standard of care profiling), and good performance status. The co-primary outcome measures are objective response and durable clinical benefit (absence of disease progression for at least 24 weeks). Eligible patients will be matched to treatment arms by a national molecular tumour board. A Bayesian adaptive design accounting for tumour histology, age and translational context will enable signals of efficacy to be identified in small numbers of patients, enabling application of learned observations for refinement of patient selection. Promising cohorts will be submitted to the CDF, who together with the NHS Clinical Policy team, will decide if a period of data collection is necessary to consider the drug as a routine treatment on the NHS. The study (opened Nov 2022) will enrol up to 650 patients over a 5 year period across the Experimental Cancer Medicine Centre network.

Clinical trial identification

NCT05722886.

Editorial acknowledgement

Legal entity responsible for the study

Cancer Research UK Centre for Drug Development.

Funding

Roche Products Ltd. (UK) are providing seven drugs as part of the clinical study and have financially supported the initial set up of the study. Novartis Pharmaceuticals UK Limited are providing funds to support a treatment arm for the study.

Disclosure

G. Middleton: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Servier, Pfizer, AstraZeneca ; Financial Interests, Personal, Advisory Role: Pfizer, Servier; Financial Interests, Personal, Speaker’s Bureau: Roche, Bristol Myers Squibb, Servier, AstraZeneca; Financial Interests, Personal, Other, Travel, Accomodation, Expenses: Pfizer; Financial Interests, Personal, Research Funding: AstraZeneca. L. Marshall: Financial Interests, Personal, Advisory Board: Bayer, Illumina, BMS, Tesaro, Eli Lilly, Novartis; Financial Interests, Personal, Invited Speaker, Co-organiser with Bayer of 2 Paediatric Preceptorship (online webinar workshops) in paediatric precision medicine. Co-chair and speaker: Bayer; Financial Interests, Personal, Other, eDMC member for 2 clinical trials: Eisai; Financial Interests, Personal, Other, eDMC member for a clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, National CI for Paediatric Pembrolizumab Phase I/II Trial: Merck; Financial Interests, Institutional, Coordinating PI, National CI for Paediatric Ponatinib Phase I trial: Incyte; Financial Interests, Institutional, Coordinating PI, National CI for Novartis Paediatric Dabrafenib/Trametinib Rollover Trial: Novartis; Financial Interests, Institutional, Coordinating PI, National CI for Roche Paediatric Idasanutlin Trial: Roche; Financial Interests, Institutional, Local PI, Local PI for Paediatric Phase I Olaparib trial: AstraZeneca; Financial Interests, Institutional, Coordinating PI, National CI for CRISP (Crizotinib) phase IB trial: Pfizer; Financial Interests, Institutional, Coordinating PI, National CI of Paediatric SCOOP phase I trial (Niraparib + Dostarlimab): GSK; Financial Interests, Institutional, Coordinating PI, National CI of Bayer Phase IB Regorafenib trial: Bayer; Financial Interests, Institutional, Local PI, Local PI of BI phase I Afatinib Trial: Boehringer-Ingelheim; Financial Interests, Institutional, Coordinating PI, National CI of Paediatric Pomalidomide phase I trial: Celgene; Financial Interests, Institutional, Coordinating PI, National CI of Paediatric Phase I Alectinib trial: Roche; Financial Interests, Institutional, Coordinating PI, National CI of Paediatric Phase I/II Ribociclib trial: Novartis; Financial Interests, Institutional, Local PI, Local PI for Pfizer Palbociclib phase II trial: Pfizer; Financial Interests, Institutional, Coordinating PI, National CI of Roche Entrectinib Phase I trial: Roche; Financial Interests, Institutional, Coordinating PI, National CI of Roche phase I Cobimetinib Trial: Roche; Financial Interests, Institutional, Local PI, Local PI for Paediatric Durvalumab/Tremelimumab phase I Trial: AstraZeneca; Financial Interests, Institutional, Coordinating PI, National CI for Roche phase I Atezolizumab trial: Roche; Non-Financial Interests, Other, Member of Scientific Advisory Board (non-remunerated): Children with Cancer UK; Other, Paediatric Lead on the CRUK-sponsored DETERMINE Platform Trial and Local PI-institutional funding received: Cancer Research UK (CRUK). A. Greystoke: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Roche, Novartis; Financial Interests, Personal, Invited Speaker: Merck, MSD, Pfizer, Janssen; Financial Interests, Institutional, Invited Speaker: MSD, Pfizer, AstraZeneca, Novartis, Achilles; Non-Financial Interests, Advisory Role: National Institue for Health and Clinical Excellence; Other, Clinical Lead for Cancer (paid position): North East Englad and Yorkshire Genomic Laboratory Hub. L. Carter: Financial Interests, Personal, Other, Consultancy: Bicycle Therapeutics, Boehringer Ingelheim, Athenex; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: Cancer research UK Centre for Drug Development; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Bicycle Therapeutics, Cellcentric, Eli Lily, Athenex, Lupin Limited, Repare Therapeutics, Cytomx therapeutics, EMD Serono/Merck KGaA, Sierra Oncology. M.D. Forster: Financial Interests, Personal, Advisory Board: Bayer, Merck, MSD, Novartis, Roche, Takeda, ultrahuman, Transgene, Ixogen, Immunotep; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, MSD, Merck; Financial Interests, Institutional, Invited Speaker: StarPharma, Roche. N. Cook: Financial Interests, Institutional, Invited Speaker: Roche, Taiho, Roche, AstraZeneca, RedX, Orion, Avacta, Bayer, Eisai, UCB, Starpharma, Boeringher, Stemline, Ergomed; Non-Financial Interests, Advisory Role: Roche. D. Hargrave: Financial Interests, Personal, Invited Speaker, Masterclass on managing NF1 associated tumours: Alexion; Financial Interests, Institutional, Expert Testimony, Preliminary meeting with NICE: Novartis; Financial Interests, Personal, Advisory Board, Advice on MTX-110: MidaTech; Financial Interests, Institutional, Advisory Board, Alectinib, Cobimetinib paediatric indications: Roche; Financial Interests, Institutional, Invited Speaker, Research Grant for a Clinical Trial Selumetinib: AstraZeneca; Non-Financial Interests, Principal Investigator, Dabrafenib and Trametinib clinical trials: Novartis; Non-Financial Interests, Principal Investigator, Tovorafenib clinical trial: Day One Therapeutics; Non-Financial Interests, Principal Investigator, Immuno-oncology trial: AstraZeneca, BMS; Non-Financial Interests, Principal Investigator, Alectinib trial: Roche; Non-Financial Interests, Principal Investigator, Avapritinib trial: Blueprint therapeutics. S. Danson: Financial Interests, Institutional, Full or part-time Employment, National Specialty Lead for Early Phase Cancer: NIHR; Financial Interests, Institutional, Other, Consultancy: Oxcia, Orion; Financial Interests, Institutional, Invited Speaker, Dante lead: NIHR; Financial Interests, Institutional, Invited Speaker, Fortitude pi: Amgen; Financial Interests, Institutional, Research Grant, Ecmc lead: Cancer research uk; Non-Financial Interests, Leadership Role, Lion steering group chair: NIHR; Non-Financial Interests, Leadership Role, Concorde steering group member: Cancer research UK. P. Roxburgh: Financial Interests, Personal, Invited Speaker: GSK, MSD; Financial Interests, Personal, Other, consultancy: Starpharma; Financial Interests, Institutional, Invited Speaker: Starpharma, Eisai, AstraZeneca, Bayer, Atrios, Immunocore, Immutep, Sierra, Mersana, Iovance, Nucana, PsiOxus, Replimune; Financial Interests, Institutional, Research Grant: Atrios; Non-Financial Interests, Institutional, Product Samples: Tesaro/GSK; Non-Financial Interests, Leadership Role, Clinical lead for cancer genomics: Scottish Strategic Network for Genomic Medicine. A.D. Beggs: Financial Interests, Personal, Advisory Role: Oxford Nanopore Technologies, Check4Cancer, Birmingham Biotech; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Oxford Nanopore Technologies; Financial Interests, Personal, Other Intellectual Property: IP on HLA Long Read seqeuncing, IP on RTF-ExPAR; Financial Interests, Personal, Other, Honoraria: Illumina; Financial Interests, Personal, Research Funding: Oxford Nanopore Technologies, AstraZeneca, Incyte. A. Chaturvedi: Financial Interests, Personal, Advisory Board, pathology advisory board-single instance (2022): Sanofi. C. Dive: Financial Interests, Institutional, Other, Research funding to centre: AstraZeneca, Amgen, Carrick Therapeutics, Merck AG, Bayer, Boehringer Ingelheim, BMS, Novartis, Celgene, Epigene Therapeutics Inc, Menarini; Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, GRAIL, Boehringer Ingelheim, IFOM. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Expert Testimony: AstraZeneca; Financial Interests, Institutional, Advisory Board: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Blueprint, Astex, Bayer, BerGenBio, Carrick, Immutep, Janssen, Novartis, Nurix, Nuvalent, Pyramid Biosciences, Roche, Seattle Genetics, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Travel expenses for congress: Immutep, Janssen. All other authors have declared no conflicts of interest.