Periodic Reporting for period 4 - MoTriColor (Molecularly guided trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of colorectal cancer (MoTriColor))
Berichtszeitraum: 2019-10-01 bis 2020-11-30
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 metastatic CRC (mCRC) patients: 1) combination of a TGFβ-inhibitor and chemotherapy 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, analysis of the immune responses, 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 mCRC 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 mCRC patients might potentially benefit from the results. Also, these results may be translated to other cancer types with equivalent gene expression patterns/ deregulated signalling pathways.
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 metastatic CRC (mCRC) patients: 1) combination of a TGFβ-inhibitor and chemotherapy 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, analysis of the immune responses, 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 mCRC 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 mCRC patients might potentially benefit from the results. Also, these results may be translated to other cancer types with equivalent gene expression patterns/ deregulated signalling pathways.
The MoTriColor work has been focused in the implantation of the screening program to identify patients with mCRC, the setting up and execution of the three clinical trials (CT1, CT2, and CT3 ) and the associated translational research. Importantly, efforts have been devoted to the dissemination and exploitation of the project results and the overall management of the project.
Regarding the screening program, we have developed three gene expression signatures that read TGFβ activated-like, BRAF mutant-like, and MSI-like profiles on FPPE tumour biopsies and we have established all the procedures and circuits to carry out the screening of patients. During the whole project 954 samples have been registered and 635 have been analysed. A total of 364 have been eligible for at least one of the three MoTriColor trials.
In parallel, the setup of the three clinical trials was concluded putting in place all the logistics and legal aspects to open the three clinical trials in Belgium, Italy, The Netherlands, and Spain. The preparative tasks also included conversations and agreements with two pharmaceutical companies that would 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 to mitigate unforeseen threats as the COVID-19 outbreak. However, this process took longer than expected due to long protocol negotiation with the pharmaceutical companies, delays in getting the approvals in the different Competent Authorities and Ethics Committees, the change of the Sponsor Principal Investigator for CT1 and CT2.
In addition, CT1 had to deal with discontinuity of the distribution of the CT1 therapy just one month before starting the recruitment: the TGFβ inhibitor. After several conversations with different pharmaceutical companies with TGFβ inhibitors in the pipeline, at the end of RP3 CT1 was not initiated.
On the other hand, CT2 was activated in all centres and, at the end of RP3, it was closed due to futility.
The European Commission granted an exceptional 8-months extension (RP4) to continue only with CT3. This was followed by a new extension of 6-months to deal with the COVID-19 related impacts. CT3 had concluded the recruitment with 46 patients enrolled. These patients had MSI-like tumours as assessed by the MSI-like FFPE signature and 46% were categorized as MSS by current diagnostic standards.
Moreover, the pipeline for the translational research has been performed. These studies will comprise different bioinformatics and biostatistical analyses, immunological studies and the monitoring of patient-specific mutations by NGS-WES of cell free DNA (cfDNA) in liquid biopsies of selected patients. cfDNA and tumour biopsy DNA have been obtained from patients selected based on RECIST and MSS/MSI status to start full genetic analysis and monitoring.
Finally, the dissemination activities have been carried out in accordance with the communication plan.
Regarding the screening program, we have developed three gene expression signatures that read TGFβ activated-like, BRAF mutant-like, and MSI-like profiles on FPPE tumour biopsies and we have established all the procedures and circuits to carry out the screening of patients. During the whole project 954 samples have been registered and 635 have been analysed. A total of 364 have been eligible for at least one of the three MoTriColor trials.
In parallel, the setup of the three clinical trials was concluded putting in place all the logistics and legal aspects to open the three clinical trials in Belgium, Italy, The Netherlands, and Spain. The preparative tasks also included conversations and agreements with two pharmaceutical companies that would 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 to mitigate unforeseen threats as the COVID-19 outbreak. However, this process took longer than expected due to long protocol negotiation with the pharmaceutical companies, delays in getting the approvals in the different Competent Authorities and Ethics Committees, the change of the Sponsor Principal Investigator for CT1 and CT2.
In addition, CT1 had to deal with discontinuity of the distribution of the CT1 therapy just one month before starting the recruitment: the TGFβ inhibitor. After several conversations with different pharmaceutical companies with TGFβ inhibitors in the pipeline, at the end of RP3 CT1 was not initiated.
On the other hand, CT2 was activated in all centres and, at the end of RP3, it was closed due to futility.
The European Commission granted an exceptional 8-months extension (RP4) to continue only with CT3. This was followed by a new extension of 6-months to deal with the COVID-19 related impacts. CT3 had concluded the recruitment with 46 patients enrolled. These patients had MSI-like tumours as assessed by the MSI-like FFPE signature and 46% were categorized as MSS by current diagnostic standards.
Moreover, the pipeline for the translational research has been performed. These studies will comprise different bioinformatics and biostatistical analyses, immunological studies and the monitoring of patient-specific mutations by NGS-WES of cell free DNA (cfDNA) in liquid biopsies of selected patients. cfDNA and tumour biopsy DNA have been obtained from patients selected based on RECIST and MSS/MSI status to start full genetic analysis and monitoring.
Finally, the dissemination activities have been carried out in accordance with the communication plan.
We have undertaken one of the most important tasks related to comprehensively select the identified patients’ populations that can be enrolled to participate in one of the trials and potentially benefit from the proposed treatments. In addition, the gene expression profiling database will be accessible to the research community and represents a unique resource for biomarker development. 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. One of these trials CT3, has been executed and the recruitment has been concluded, offering an innovative and cost-effective therapeutic approach to 46 MSI-like patients (46% of them identified as MSS-real by current diagnostic standards).
This project has also allowed us to set up technologies of a high impact on cancer immunotherapy. These results represent a breakthrough towards understanding the tumour antigens recognized by the immune system of mCRC patients and how they evolve with immunotherapy in responding and non-responding patients. This will be key to improve the outcome of immunotherapy in mCRC patients and in cancer patients in general.
In addition, we have shown the possibility of successfully monitoring the response to the treatment using the circulating tumour DNA (ctDNA) in the blood. Through the high sensitivity NGS liquid biopsy analysis, we have reported partial or complete molecular response in ‘responder’ patients and increase of tumour content in ‘non responder’ ones to Motricolor CT3 therapy.
Regarding the social implications, we can state that an important number of patients in our centres (which cover a wide mCRC 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 the treatments they were receiving did fail. Specifically, 46 patients have been recruited in CT3.
In terms of economic impact, we believe that it is too early to perform any overall assessment. Once CT3 is concluded, we will carry out parallel studies to analyse the impact of the potential benefits of the treatments in the selected population.
In parallel, the consortium has been working in having all the trials activated in all clinical sites. One of these trials CT3, has been executed and the recruitment has been concluded, offering an innovative and cost-effective therapeutic approach to 46 MSI-like patients (46% of them identified as MSS-real by current diagnostic standards).
This project has also allowed us to set up technologies of a high impact on cancer immunotherapy. These results represent a breakthrough towards understanding the tumour antigens recognized by the immune system of mCRC patients and how they evolve with immunotherapy in responding and non-responding patients. This will be key to improve the outcome of immunotherapy in mCRC patients and in cancer patients in general.
In addition, we have shown the possibility of successfully monitoring the response to the treatment using the circulating tumour DNA (ctDNA) in the blood. Through the high sensitivity NGS liquid biopsy analysis, we have reported partial or complete molecular response in ‘responder’ patients and increase of tumour content in ‘non responder’ ones to Motricolor CT3 therapy.
Regarding the social implications, we can state that an important number of patients in our centres (which cover a wide mCRC 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 the treatments they were receiving did fail. Specifically, 46 patients have been recruited in CT3.
In terms of economic impact, we believe that it is too early to perform any overall assessment. Once CT3 is concluded, we will carry out parallel studies to analyse the impact of the potential benefits of the treatments in the selected population.