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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MoTriColor (Molecularly guided trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of colorectal cancer (MoTriColor))

Teaser

Summary

Colorectal cancer (CRC) is increasingly being recognized as a heterogeneous disease with distinct molecular subtypes. These subtypes have different biological processes at the basis of their disease and consequently their prognosis and responses to therapy are also different. We have developed molecular diagnostic assays using a single platform on routine FFPE tumour biopsies. These assays identify gene expression profiles with distinct prognosis and drug response phenotypes (TGFÎ²-like (c-type), BRAF mutant-like, and MSI-like).
Our overall objective is to develop targeted therapies for these specific populations more effective than the current available therapies, that do not take advantage of molecular classification of the disease to select treatments. We therefore propose to perform 3 multi-centre open-label phase II studies based on solid preclinical evidence and a sound scientific rationale for these subgroups of CRC patients: 1) combination of Galunisertib (TGFÎ²-inhibitor) and Capacetabine in patients presenting a TGFÎ²-like signature; 2) Vinorelbine in patients with a BRAFm like signature; and 3) an immunotherapy atezolizumab in combination with bevacizumab in patients with a MSI-like signature. The primary objectives of these studies are to determine the clinical efficacy (progression-free survival and overall response rate as primary endpoints, depending on the trial), safety and tolerability of the experimental treatments in these molecularly selected populations. Molecular analysis at the beginning of treatment and monitoring by liquid biopsies (blood) might reveal further biomarkers that predict response in retrospective analysis.
The project outcomes may have a significant impact in CRC patients with poor-risk prognosis worldwide as 40-50% of them could present gene expression profiles matching one of the 3 approaches. Around 40,000 European CRC patients might potentially benefit from the results. Also, these may be translated to other cancer types with equivalent gene expression patterns/ deregulated signalling pathways.

Work performed

During the first 18 months of the project, most of the work has been focused in setting up both the screening of patients and the three clinical trials.
Regarding the screening, we have developed three gene expression signatures that read TGFÎ²-like, BRAF-like, and MSI-like FFPE profiles on FPPE tumor biopsies. In addition, all the procedures and circuits to carry out the screening of patients have been established, and two batches of tumor samples have already been analysed, showing that 55.3% of the patients are eligible to at least one of the three clinical trials (one for each of the above mentioned signatures).
In parallel, the setup of the three clinical trials has been almost completed, putting in place all the logistics and legal aspects to open the three clinical trials in Belgium, Italy, Netherlands, and Spain in the coming months. These preparative tasks also include conversations and agreements with two pharmaceutical companies that will provide novel drugs for two of the three trials. The MoTriColor clinical trials will provide novel therapeutic opportunities to patients with these specific profiles.
On top of that, the pipeline for the translational research has been defined. These studies will comprise different bioinformatics and biostatistical analyses, immunological studies and the monitoring by liquid biopsies. These tasks will start with the opening of the trials and may reveal further biomarkers for response prediction.
Finally, the dissemination activities have been carried out in accordance with the project communication plan. During this period the main objective has been raising awareness of the project and preparing the future dissemination and exploitation of the results.

Final results

During this first reporting period, we have undertaken one of the most important tasks related to comprehensively select the identified patientsâ€™ populations which are entitled to enter the trials and potentially benefit from the proposed treatments. Details about these screening tasks are provided below. In parallel, everything is ready to have all the trials approved by the IRBs in most clinical sites. With concern to social implications at this stage, we can already say that an important number of patients in our centres (which cover a wide CRC population in our countries â€“ as many are visited as second opinion), patients with poor prognosis or at advance disease stages, have been offered new therapeutic options if their current treatments fail and they relapse. Specifically, 21 patients have already been identified for the three therapeutic approaches.
In terms of economic impact, we believe that it is too soon to perform any overall assessment or attire any conclusions. During the second reporting period (RP2), when the clinical trials will be performed, we will carry out parallel studies to analyse the impact of the potential benefits of the treatments in the selected population.