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CSM collaborator Sean O’Cathail took CEDAR, an adaptive phase I trial in rectal cancer, to a Europe-wide protocol development workshop in June 2017, where it tied for most innovative protocol.

Composite image in blues and purples of the Oxford skyline and researchers working in laboratories and healthcare, overlaid with the text ‘harnessing Oxford’s world-leading science to cure cancer.

CSM statisticians are working with CRUK/MRC Oxford Institute for Radiation Oncology’s Maria Hawkins and Sean O’Cathail to set up an adaptive model-based phase I trial of an oncolytic virus with chemotherapy in rectal cancer. O’Cathail took CEDAR to the ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research, a Europe-wide protocol development workshop. From 10 nominees out of the 83 participants at the workshop, CEDAR tied with two other protocols for most innovative protocol.

It is so important to take the right dose forward, and this is one of the major benefits of these more advanced model-based trials. - Jane Holmes, CSM medical statistician

“The MCCR workshop was an excellent experience to develop CEDAR with input from world renowned faculty,” said O’Cathail. “I believe CEDAR stood out in a strong field as it offers a paradigm shift in radiosensitization strategy, multiple translational outputs, and a novel statistical design. The experience really helped me to focus on the key objectives of the trial and has hugely benefitted the trial’s development.”

CEDAR will test the safety and biological effects of combining a virus able to target cancer cells (EnAdenotucirev) with standard chemoradiotherapy in locally advanced rectal cancer. Enadenotucirev has been shown to selectively replicate in cancer cells of epithelial origin, which includes colorectal cancer. Once it enters a cell, the virus uses the cell to replicate itself, ultimately killing the infected cell by oncolysis (a method which essentially bursts the cancer cell). The body’s natural immune system is stimulated by the dying cancer cells, which may in turn complement the action of standard chemoradiotherapy.

Phase I trials investigate which dose of a new drug patients should take. Unlike most phase I trials, CEDAR will not just monitor when the dose is too high and can harm the patient (toxicity). It will also check whether there is a point when higher doses no longer give more benefit (efficacy).

CSM statisticians are part of a UK-wide movement to encourage more clinical trialists to use adaptive model-based designs in their phase I dose finding trials, so that fewer patients are treated at sub-optimal doses and the right dose is found more often. Most phase I studies use simple rules to find the drug dose to take forward to phase II trials. CEDAR will use a statistically advanced design called model-based dose-escalation. Instead of simple rules, the model-based design uses all of the patient data already collected in the trial to decide what dose to give the next patient. These more advanced designs recommend the right dose at the end of the trial more often than rule-based designs. They are also more flexible, taking into account the specific requirements of the disease and treatment when deciding how quickly to change the dose from participant to participant.

Jane Holmes, CSM statistician for CEDAR, explains more: “A phase I trial is the first time a drug is tested in humans, and we are primarily interested in testing whether the drug is safe. If the drug is successful at phase I, we can then look at whether it may be beneficial in further trials. If we test the wrong dose in later phases, a good drug might fail. It is so important to take the right dose forward, and this is one of the major benefits of these more advanced model-based trials.”

The ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research is an educational programme that introduces junior clinical oncologists in any oncology subspecialty to the principles of good clinical trial design. Over its 19 years of existence, it has trained hundreds of clinical oncologists to successfully set up and run a high quality clinical trial. Every participant at a workshop brings a draft protocol and leaves with a protocol ready to implement.

The other two winners of most innovative protocol were Tanja Eggersmann of the University of Munich, whose phase III trial evaluates an e-health-based mechanism for observing patient-reported outcomes in early breast cancer (eHOb-PRO), and Maxime van der Valk of Leiden University Medical Centre, whose phase II trial studies the feasibility of a tumour-targeted fluorescent tracer to enhance chemo-radiotherapy treatment for rectal cancer.

CEDAR (EudraCT number 2017-003501-18) is supported by Cancer Research UK (C43735/A24474) and PsiOxus Therapeutics Limited and sponsored by the University of Oxford. The team expects to open to recruitment in 2018.

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