Cell-Free DNA-Based Multi-Cancer Early Detection Test in an Asymptomatic Screening Population (NHS-Galleri): Design of a Pragmatic, Prospective Randomised Controlled Trial

Richard D Neal, Peter Johnson, Christina A Clarke, Stephanie A Hamilton, Nan Zhang, Harpal Kumar, Charles Swanton, Peter Sasieni, Richard D Neal, Peter Johnson, Christina A Clarke, Stephanie A Hamilton, Nan Zhang, Harpal Kumar, Charles Swanton, Peter Sasieni

Abstract

We report the design of the NHS-Galleri trial (ISRCTN91431511), aiming to establish whether a multi-cancer early detection (MCED) test that screens asymptomatic individuals for cancer can reduce late-stage cancer incidence. This randomised controlled trial has invited approximately 1.5 million persons and enrolled over 140,000 from the general population of England (50-77 years; ≥3 years without cancer diagnosis or treatment; not undergoing investigation for suspected cancer). Blood is being collected at up to three annual visits. Following baseline blood collection, participants are randomised 1:1 to the intervention (blood tested by MCED test) or control (blood stored) arm. Only participants in the intervention arm with a cancer signal detected have results returned and are referred for urgent investigations and potential treatment. Remaining participants in both arms stay blinded and return for their next visit. Participants are encouraged to continue other NHS cancer screening programmes and seek help for new or unusual symptoms. The primary objective is to demonstrate a statistically significant reduction in the incidence rate of stage III and IV cancers diagnosed in the intervention versus control arm 3-4 years after randomisation. NHS-Galleri will help determine the clinical utility of population screening with an MCED test.

Keywords: cancer screening; cell-free nucleic acids; efficient design; liquid biopsy; multi-cancer early detection; population screening; randomised controlled trial.

Conflict of interest statement

R.D.N. provides his services as Co-Chief Investigator to the NHS-Galleri trial through university consultancy funded by GRAIL, LLC, a subsidiary of Illumina, Inc., to the University of Exeter; both he and the University of Exeter financially benefit from this partnership. C.C., N.Z. and H.K. are employees of GRAIL, LLC, a subsidiary of Illumina, Inc., and hold stock in Illumina, Inc. S.H. is an employee of Adela, Inc., was an employee of GRAIL, LLC, a subsidiary of Illumina, Inc., and holds stock in Illumina, Inc. C.S. provides his services as Co-Chief Investigator to the NHS-Galleri trial through university consultancy funded by GRAIL, LLC, a subsidiary of Illumina, Inc.,to University College London Business, for another study; is an AstraZeneca advisory board member and Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials; C.S. is paid member of GRAIL’s Scientific Advisory Board (SAB); received grant funding from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae, and Ono Pharmaceutical; receives consultant fees from Achilles Therapeutics (also SAB member), Genentech, Medixci, Roche Innovation Centre Shanghai, Bicycle Therapeutics (also SAB member), and the Sarah Canon Research Institute; and has received honoraria from Amgen, AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Illumina, Roche-Ventana, Metabomed (until July 2022); had stock options in Apogen Biotechnologies and GRAIL until June 2021; currently has stock options in Epic Bioscience, Bicycle Therapeutics, and Achilles Therapeutics; and is co-founder of Achilles Therapeutics. P.S. is a paid member of GRAIL’s Scientific Advisory Board and the Director of the The Cancer Research UK and King’s College London Cancer Prevention Trials Unit that is contracted by GRAIL, LLC, a subsidiary of Illumina, Inc. to run the NHS-Galleri trial, and receives consultant fees from Roche. P.J. receives honoraria from Genmab, Epizyme, and InCyte, and acts as a consultant for Epizyme.

Figures

Figure 1
Figure 1
An overview of the NHS-Galleri trial. GP, general practitioner; MCED, multi-cancer early detection; NHS, National Health Service. * Individuals with non-melanoma skin cancer and individuals with prostate cancer whose only treatment is active surveillance are not excluded.
Figure 2
Figure 2
(A) Map of the eight participating NHS Cancer Alliances and (B) the IMD score distribution of targeted GP practices identified by NHS DigiTrials. (A) England has a total of 21 NHS Cancer Alliances. The regions shaded in purple are the eight participating NHS Cancer Alliances in the NHS-Galleri trial. (B) The IMD score distribution is from targeted GP practices identified by NHS DigiTrials. NHS DigiTrials invited eligible participants registered with these GP practices. The bar graph represents the percent of GP practices (y-axis) in each Cancer Alliance based on the IMD score (x-axis). IMD decile: 1 = most deprived, 10 = least deprived. GP, general practitioner; IMD, Index of Multiple Deprivation; NHS, National Health Service.

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