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Molecularly guided trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of colorectal cancer (MoTriColor)

Periodic Reporting for period 3 - MoTriColor (Molecularly guided trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of colorectal cancer (MoTriColor))

Reporting period: 2018-10-01 to 2019-09-30

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 (TGFβ activated-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, which 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 (TGFβ-inhibitor) and Capacetabine in patients presenting a TGFβ-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.
Until September 2019, most of the work has been focused in setting up and implementing both the screening of patients and the three clinical trials.
Regarding the screening, we have developed three gene expression signatures that read TGFβ activated-like, BRAF mutant-like, and MSI-like profiles on FPPE tumor biopsies and we have established all the procedures and circuits to carry out the screening of patients. During part of the second reporting period the screening program was stopped because CT1 and CT2 trials were not active. Afterwards, from October 2018 to August 2019, the screening was reactivated with the limitation to MSI-real until all clinical trials were activated in all sites. From August 2019 onwards the screening has been fully operative. To the date 583 arrays have been used to provide for 398 patients a result, showing that 60.8% 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 CT2 and CT3 has been completed and CT1 is almost concluded. These preparative tasks also included conversations and agreements with two pharmaceutical companies that will provide novel drugs for two of the three trials. In addition, amendments have been performed in the trials protocols in order to adapt them to new safety requirements, the current regulation, and the consortium needs.
CT2 is activated in all centres and ready to start recruitment. Until now, 1 patient has already been recruited in CT2. In addition, CT3 is activated in all sites and has already recruited 36 patients in the trial. These patients had MSI-like tumors as assessed by the MSI-like FFPE signature and 42.4% were categorized as MSS by current diagnostic standards.
Moreover, the pipeline for the translational research has been defined. These studies will comprise different bioinformatics and biostatistical analyses, immunological studies and the monitoring of patient-specific mutations by NGS-WES of cfDNA in liquid biopsies of selected patients. Cell free DNA and genomic DNA have been obtained from patients selected based on RECIST and MSS/MSI status to start genetic analysis and monitoring.
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.
We have undertaken one of the most important tasks related to comprehensively select the identified patients’ populations that can be enrolled to enter one of the trials and potentially benefit from the proposed treatments. Details about these screening tasks are provided in Part B. In parallel, the consortium has been working in having all the trials activated in all 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 – 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, 36 patients have already been recruited in CT3 and 1 patient in CT2.
In terms of economic impact, we believe that it is too soon to perform any overall assessment. Once the clinical trials are performed, we will carry out parallel studies to analyse the impact of the potential benefits of the treatments in the selected population.