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  • Periodic Report Summary 3 - MERCURIC (A Phase Ib/II study of MEK1/2 inhibitor PD-0325901 or MEK-162 with cMET inhibitor PF-02341066 in RASMT and RASWT (with aberrant c-MET) Colorectal Cancer Patients.)

Periodic Report Summary 3 - MERCURIC (A Phase Ib/II study of MEK1/2 inhibitor PD-0325901 or MEK-162 with cMET inhibitor PF-02341066 in RASMT and RASWT (with aberrant c-MET) Colorectal Cancer Patients.)

Project Context and Objectives:
Colorectal Cancer (CRC) is any cancer of the large bowel, including colon and rectal cancer. It is a common, and often deadly form of cancer. In Europe, around 450,000 people are diagnosed with CRC every year. With approximately 200,000 deaths per year, it remains the second most common cause of cancer death. More than half of all CRC patients develop cancer in other parts of their bodies. Only 5% of CRC patients live longer than five years after their diagnosis.

Early diagnosis is key to effective cancer treatment. CRC has no visible symptoms until it is very advanced, and may be too late for surgery. Spread of the cancer to other parts of the body (metastasis) is also common in CRC. Chemotherapy and radiotherapy are also used to treat CRC but the long-term survival outcome for many patients is very poor. While chemo- and radiotherapy are widely used to treat CRC, many patients do not respond to these standard treatments. Current treatments are ineffective because they are based on “one-size-fits-all” approaches, but cancer is a heterogeneous disease - cancer cells are different for different patients and even at different places within the same patient. Cancer cells also change with time, and can become resistant to treatments that were once effective. While some patients may be cured by current treatments, many patients do not benefit at all, yet may still suffer the unpleasant side effects associated with a particular therapy. Giving patients a therapy that is not effective for them also means that they lose precious time before a more effective second-line treatment is given.

Cancer researchers are learning more about the molecular and genetic heterogeneity of CRC, and developing tests to profile cancer in individual patients. To provide CRC patients with better treatments, new treatments must be developed using this knowledge and tested in selected groups of patients most likely to benefit. In particular novel treatments are needed for subgroups of CRC patients with poor outcome, such as CRC patients with RAS mutated tumours.

For MErCuRIC, a clinical trial of an innovative combination of treatments is being carried out in several clinical centres across Europe. Earlier research from MErCuRIC researchers has indicated that one gene, called MET, cause RAS mutated bowel cancer cells to become resistant to treatments used against the disease, in particular anti-MEK treatments. The study further showed that that these bowel cancers switch on a survival mechanism when they are treated with drugs that target faulty MEK genes. But when the researchers added drugs that also block the MET gene, the bowel cancer cells died. The MErCuRIC team have started a new approach to target these two genes in three specific groups of CRC patients, in particular CRC patients with RAS mutated tumours and abnormal MET expression. Preliminary results from the project’s early phase clinical trial show that this novel combination is well tolerated in heavily pre-treated cancer patients. This “personalised medicine” clinical trial is the first step towards having the new combination therapy used in clinics. The project will also create a biobank of clinical samples from the trial that can be used to answer future research questions.

MErCuRIC is also developing new blood tests to predict whether a particular patient will respond to the innovative combination therapy, supporting a stratified medicine approach tailoring treatments to patient subgroups. Patients that are unlikely to respond to the therapy will be identified, saving them from unnecessary and ineffective treatments, and enabling them to start a more effective treatment without delay. The goal of a stratified medicine approach to CRC treatment is to deliver improved survival outcomes and better quality of life for patients and change current clinical practices in the treatment of the disease.

Current treatment approaches often involve painful and invasive tumour biopsies. As an alternative to biopsies, MErCuRIC is developing new blood tests to track the response of individual patients to treatment. These new tests will allow clinicians to detect the emergence of resistance to therapy and switch patients to more effective alternative therapies, improving patient outcomes.

Patients are at the center of the MErCuRIC project. The consortium recognizes the importance of ensuring patient input into the clinical trial, and of communicating our results to CRC patients across Europe. For these reasons, MErCuRIC has established a Public Patient Initiative and engaged with key patient organizations across Europe, including EuropaColon and the European Cancer Patient Coalition.

Project Results:
MErCuRIC has already completed a phase Ia study of the innovative combination of MEK inhibitor (PD-0325901) with the MET inhibitor (Crizotinib), recruiting patients from four trial sites across Europe in the United Kingdom (Oxford and Belfast), Spain (Barcelona) and Belgium (Antwerp). The results of this study showed that the two drugs can be given together safely at doses that have a clinical effect in patients. The results from this study were presented at a number of international cancer conferences (ASCO, ESMO, NCRI).

A second phase Ia study with another MEK inhibitor (Binimetinib) and MET inhibitor (Crizotinib) has also been completed, identifying the maximum dose that can be safely given to patients. In a follow-on phase Ib study, specific sub-groups of patients with mutated RAS genes or RAS wild type with abnormal MET expression are now being treated with this combination therapy to see if they respond.

In order to develop better, personalised treatments for CRC patients, clinicians and researchers need to learn about individual profiles of cancer and develop ways to identify different sub-groups of patients. MErCuRIC researchers have developed a scoring system to identify sub-groups of patients with CRC. They are using this scoring system to select patients for recruitment to the on-going phase Ib study, as well as to tracking any changes in the score during treatment. The team has also developed a number of novel genetic tests that will allow us to measure tumour mutations in blood and tissue samples, so that we can better identify groups of patients most likely to benefit from specific treatments and better understand how resistance to treatment arises. Over 25 publications on our pre-clinical work have been published to date.

The MErCuRIC clinical trials involve the collection and analysis of a large number of blood and tissue samples. A centralised bio-bank has been set up to store the samples obtained during the project. These samples will be analysed as part of the clinical trial, but will also be stored for use in other research in future, ensuring that the greatest possible scientific value is obtained from the trial.

In addition to a large number of blood and tissue samples, the trial will generate a large volume of data at multiple sites. A central database to securely hold all the data has been established and will allow the data to be analysed consistently. Using this database, MErCuRIC researchers will be able to work together to answer important clinical and research questions.

MErCuRIC researchers have expanded the Public Patient Initiative (PPI) in collaboration with local patient representatives and patient organisations at the European level, including EuropaColon and the European Cancer Patient Coalition. MErCuRIC was presented at the 1st European Alliance for Personalised Medicine (EAPM) Congress, with a particular emphasis on the PPI aspects of the project. Patient perspectives have been shared on our website and an explainer video of the project has been created and shared widely.

Potential Impact:
MErCuRIC is investigating a novel stratified medicine approach in mCRC patients with poor prognostic indicators, which aims to significantly improve patient outcomes. Recent advances in treatment targeting pathway biology has brought some improvements in outcomes, but drug resistance is common and severely limits the success of these approaches. New drugs circumventing treatment resistance are urgently needed.

The combination therapy for mCRC investigated by MErCuRIC has the potential for significant clinical and scientific impact, as well as economic benefits for health care systems and the European diagnostics industry.

Clinical impact: MErCuRIC is examining the benefit of a novel combination therapy based on discovery research by MErCuRIC researchers. The therapy targets a subset of mCRC patients for whom no currently available therapy is effective. A novel, stratified medicine approach is being developed to treat mCRC patients with poor prognoses, which aims to significantly impact on patient outcomes. In addition to improving patient survival, the stratified medicine approach will improve patient quality of life by sparing patients from the side effects of treatments that would be ineffective against their individual cancer.

Research impact: MErCuRIC will deliver advances in the area of blood biomarkers through research in Next Generation Sequencing and circulating tumour DNA - such biomarkers will be relevant to the patient population targeted by the project but will also have the potential to improve diagnosis and surveillance for other major cancers, including lung, breast and prostate. MErCURIC will also deliver a transcriptomic-based predictive biomarker profile that can be validated further in phase II and phase III clinical trials.

In addition, state-of-the-art, patient-relevant model systems will be developed that will allow clinicians to ‘test before they treat’ and avoid giving treatments to patients who will not respond to them. These model systems will not only benefit the stratified patient population in this project, but will also serve as a novel paradigm for future drug discovery/development approaches for other major cancers.

Economic impact: The European cancer diagnostics industry will benefit from the project through the development of new diagnostic assays that build on MErCuRIC research findings. This impact will be achieved through our industrial partners and collaborators.

There will also be associated economic benefits for healthcare systems. CRC is an age-related disease, particularly relevant for the ageing populations of Europe and the Western World, with over one million new cases and over 680,700 deaths each year. The stratified medicine approach of MErCuRIC will be more cost-effective than a “one size fits all” approach - patients will receive treatment that will be effective against their individual cancer as a first line treatment.

List of Websites:
www.mercuric.eu

Reported by

THE QUEEN'S UNIVERSITY OF BELFAST
United Kingdom

Subjects

Life Sciences
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