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In commemoration of World Cancer Day on 4 February 2016, CSM statisticians present a TiTE-CRM phase I trial design for testing a chemoradiotherapy intervention in oesophageal cancer.

Model based trial design for more efficient phase i trials Maria Hawkins
Computed tomography image of a radiotherapy plan for oesophageal cancer (tumour shown in red), delivered using intensity modulated radiotherapy. The radiotherapy target area is shown in yellow.

One of the most important tools in cancer treatment is chemoradiotherapy, but traditional phase I trial designs have made testing chemoradiotherapy protocols particularly challenging. Centre for Statistics in Medicine (CSM) statisticians are applying a little-used trial design in the phase I trial CHARIOT to overcome these challenges. Clever use of statistics means patients can be recruited more quickly and are more likely to be given the optimum dose than in a traditionally designed trial. The resulting Time to Event Continual Reassessment Method (TiTE-CRM) phase I design will allow clinicians to test a new chemoradiotherapy protocol in a realistic timeframe.

Early phase cancer trials are beset with numerous challenges. Producing accurate, reliable and timely statistics is key to developing new therapies in particular and improved healthcare standards in general. - CSM Medical Statistician

Phase I trials aim to find an optimal safe dose of the treatment under investigation. In traditional trials, trial participants receive a pre-assigned dose of a drug and are monitored during and after treatment for any side effects. The CRM design is different: when a new participant joins the trial, a statistical model and information on the previously recruited participants are used to assign their dose. The advantage is that more of the trial participants get a dose close to the optimum dose, and fewer participants receive a much higher or lower dose than in a traditional trial.

Traditional trial design also requires researchers to wait until the treatment follow-up period is complete for each patient before they can recruit the next patient. Radiotherapy trials have a particularly long follow-up period for each patient, as radiotherapy side effects can take up to 3 to 6 months to appear. Statistics can shrink that wait.

The TiTE aspect of the design allows new participants to be recruited while existing participants are still being followed up. All of the information available on the previous and current participants is used by the statistical model to work out whether the trial is proceeding safely before assigning the dose for the new patient. The resulting TiTE-CRM trial is much shorter than in a traditional design. This design requires extensive simulations and much more thought by designers before the trial begins than a traditional trial, to capture its behaviour and capabilities.

CHARIOT is the first trial examining the combination of radiotherapy, chemotherapy and the Ataxia Telangiectasia Mutated Rad3-related (ATR) inhibitor in patients with oesophageal cancer. The primary objective is to work out which dose to use in further trials. The TiTE-CRM design means a far more extensive set-up period than traditional trials for the statisticians – and a more efficient, faster trial for its participants.

This news item is part of a series on the cancer research conducted and supported by the Centre for Statistics in Medicine, in commemoration of World Cancer Day on 4 February 2016. Read the introduction to the series here, about two trials on Barrett's Oesophagus here, and about a new trial on pancreatic cancer here.