Identification of Molecular Biomarkers for Cancer Target Therapy Efficacy

Study Overview
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Brief Summary
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This is a prospective trial for a computation-based efficacy prediction method for anticancer target therapies. The original computational algorithm utilizes individual transcriptome data of a cancer sample and assesses changes at the level of gene expression and intracellular signaling pathways. By applying the database of known molecular targets of anticancer target drugs it allows to rank potential efficacies of target drugs.

Detailed Description
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Original computational algorithm Oncobox was developed to determine molecular features of individual tumors. It represents the solution for a personalized selection of target anticancer therapies. The method is based on the analysis of gene expression profile of a cancer sample in comparison with the corresponding normal tissue biosamples in order to select the most effective molecular targets for their inhibition and, accordingly, to identify more effective target drugs for cancer treatment. Histological material obtained from cancer patients during surgery or core-needle biopsy as part of standard treatment will be used for the analysis. Total RNA extracted from the tumor material will be subjected to next-generation sequencing (NGS). By comparing transcriptome profile of the tumor sample with the profiles of the corresponding normal tissue samples the rate of molecular pathways activation/deactivation will be calculated, as well as the case-to-normal ratios for the individual gene products - molecular targets of drugs. Based on these data, each target drug will be assigned with a score reflecting its potential efficacy for each individual tumor treatment. A drug with the score value above 0.1 will be considered potentially effective, a drug with the score value equal to or below 0.1 - as potentially ineffective. Following Oncobox test, 130 target anticancer drugs will be rated according to their predicted effectiveness (see the list of eligible target drugs below). This information will be fully available to a patient and his/her doctor. The doctor will prescribe treatment according to his/her consideration, e.g. based on the standards of care and the patient's life indications. After the appointment of therapy, the patients will be divided naturally into the following three observation groups. The first group will be formed from patients receiving target drugs with the score value above 0,1 as monotherapy or in combination. The second group - patients receiving only non-target drugs or target drugs with the score value equal to or below 0,1 as monotherapy or in combination. Third group will be formed by patients receiving palliative care. Within this study, these three groups will be compared by response to the therapy according to the results of instrumental studies, by time to progression and by time to progression compared to the previous line of therapy (if any). Additionally, overall survival will be measured in all three groups. Eligible target drugs: Abemaciclib (LY2835219) Afatinib Aflibercept Alectinib Alemtuzumab Alitretinoin Anastrozole Apalutamide, ARN-509 Arsenic trioxide Atezolizumab Avelumab Axitinib Belinostat Bevacizumab Bexarotene Bicalutamide Binimetinib (MEK162) Blinatumomab Bortezomib Bosutinib Brentuximab vedotin Brigatinib Cabazitaxel Cabozantinib Carfilzomib Ceritinib (Zykadia, LDK378) Cetuximab Cobimetinib Crizotinib CYT387 (Momelotinib) Dabrafenib Daratumumab Dasatinib Degarelix Denileukin diftitox (Ontac) Denosumab Docetaxel Dovitinib Durvalumab Elotuzumab Encorafenib Enzalutamide Erlotinib Estramustine Everolimus Exemestane Flavopiridol (Alvociclib) Foretinib Fulvestrant Ganetespib (STA-9090) Gefitinib Goserelin Homoharringtonine (Omacetaxine mepesuccinate) Ibritumomab tiuxetan Ibrutinib Idelalisib Imatinib Inotuzumab ozogamicin Ipilimumab Ixabepilone Ixazomib (MLN9708) Lapatinib Lenalidomide Lenvatinib Letrozole Leuprolide Lomustine Masitinib Medroxyprogesterone acetate (MPA) Megestrol Methyltestosterone Midostaurin Mogamulizumab Moxetumomab pasudotox Necitumumab Nilotinib Nilutamide Nimotuzumab Nintedanib (BIBF 1120) Niraparib Nivolumab (BMS-936558) Obinutuzumab Ofatumumab Olaparib Olaratumab Osimertinib Paclitaxel Palbociclib Panitumumab Panobinostat Pazopanib Pembrolizumab Perifosine Pertuzumab Pomalidomide Ponatinib Ramucirumab (Cyramza) Regorafenib Ribociclib Rigosertib Rituximab Romidepsin Rucaparib Ruxolitinib Selumetinib Siltuximab Sonidegib (LDE225) Sorafenib Sunitinib Tamoxifen Tecemotide (Emepepimut-S, L-BLP25) Temozolomide Temsirolimus Thalidomide Tivantinib Tivozanib Toremifene Trametinib (Mekinst) Trastuzumab Trebananib Vandetanib Veliparib Vemurafenib Venetoclax Vinblastine Vincristine Vindesine Vinorelbine Vismodegib Vorinostat

Official Title
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Identification of Molecular Biomarkers for Cancer Target Therapy Efficacy

Conditions
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Cancer

Intervention / Treatment
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* Other: RNA sequencing
* Other: Transcriptome analysis
* Drug: target drug with the score above 0,1
* Drug: target drug with the score equal or below 0,1
* Drug: non-target drug
* Drug: palliative care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults, diagnosed with cancer; Age 18 - 80; Patients who previously received anticancer treatment within the standard care, patients for whom standard therapy was not indicated or patients refused to receive standard therapy. Patients could receive an unlimited number of treatment lines before this study; Available formalin fixed, paraffin-embedded (FFPE) samples of cancer tissue. The material should be confirmed by a certified pathologist, the sample taken for the analysis should contain at least 70% of tumor cells; Anticipated survival of at least 3 months since the patient's inclusion in the current investigation; Patients who have signed an informed consent. Exclusion Criteria: Anticipated survival of less than 3 months since the patient's inclusion in the current investigation; Lack of tumor biopsy material, inability to obtain a new tumor biopsy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>Patients receiving target drugs with the score value above 0,1 as monotherapy or in combination | Other: RNA sequencing<br>* Next Generation Sequencing of RNA from tumor samples, rRNA-depleted.<br>* Other names: RNA-seq;Other: Transcriptome analysis<br>* Analysis of RNA-seq data using the Oncobox algorithm.<br>Drug: target drug with the score above 0,1<br>* target drug with the score above 0,1<br>|
| Group 2<br>Patients receiving only non-target drugs or target drugs with the score value equal to or below 0,1 as monotherapy or in combination | Other: RNA sequencing<br>* Next Generation Sequencing of RNA from tumor samples, rRNA-depleted.<br>* Other names: RNA-seq;Other: Transcriptome analysis<br>* Analysis of RNA-seq data using the Oncobox algorithm.<br>Drug: target drug with the score equal or below 0,1<br>* target drug with the score equal or below 0,1<br>Drug: non-target drug<br>* non-target drug<br>|
| Group 3<br>Patients receiving palliative care | Other: RNA sequencing<br>* Next Generation Sequencing of RNA from tumor samples, rRNA-depleted.<br>* Other names: RNA-seq;Other: Transcriptome analysis<br>* Analysis of RNA-seq data using the Oncobox algorithm.<br>Drug: palliative care<br>* palliative care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response | Tumor response according to the results of instrumental studies | 2 years | 
| Time to progression | Time to progression | 2 years | 
| Time to progression compared to the previous therapy lane | Time to progression compared to the previous therapy lane | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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target therapy, NGS, RNAseq, mRNA, transcriptome analysis, signaling pathway, intracellular molecular pathway, Oncobox, Next generation sequencing, RNA sequencing, biomarkers