Trans-RosaLEE Study: a Biomarker-directed, Translational Study

Study Overview
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Brief Summary
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Hormone receptor (HR)-positive and HER2-negative (HR+/HER2-) metastatic/advanced breast cancer (mBC) is a major public health issue. During the last decades, a therapeutic challenge was to overcome the tumor's resistance to endocrine therapy (ET). Thanks to a better understanding of the molecular mechanisms of this resistance, effective new treatments have been developed, such as Kisqali® (ribociclib), a molecularly targeted therapy. This treatment blocks the growth and division of cancer cells by blocking proteins called CDK4/6 located inside the cell. This treatment, taken in combination with ET, blocks the harmful effect of hormones (estrogen) on cancer cell proliferation, and represent the standard first-line treatment of patients with HR+/HER2- mBC. But, as with any treatment, it is expected that some patients will have a good response and their disease will be stabilized or even in remission, while other patients will not benefit from treatment and will relapse. In order to make progress, it is necessary to identify pre-therapeutic markers predictive of response to this treatment and the molecular mechanisms of this resistance set up by the tumor before or under the effect of the treatment. The Trans-RosaLEE study aims to fill this gap by providing high-throughput molecular profiling (DNA and RNA) of a collection of tumor and blood samples from patients with RH+/HER2- mBC scheduled to start treatment with Kisqali® + ET. Samples will be collected just prior to initiation of therapy (pre-therapy) and just after discontinuation of therapy in the event of disease progression (post-therapy). The main objectives of the TransRosaLEE study are : to determine if Kisqali® + ET treatment causes changes in the DNA and/or RNA genes of tumor; to identify whether there is a molecular signature that would predict clinical outcome of patients treated with Kisqali® + ET (tumor response, survival); to identify alterations in tumor's genes that could be targeted by a specific treatment and that would allow, in case of progression of the disease, to set up a new adapted treatment. The TransRosaLEE study is a collaborative study between the Paoli-Calmettes Institute (France, Marseille) and the pharmaceutical group Novartis. It will take place in up to 90 healthcare institutions in France, and 241 patients will be enrolled. It is closely linked to the non-interventional study RosaLEE promoted by Novartis.

Official Title
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Trans-RosaLEE Study: a Biomarker-directed, Translational Study of High-throughput Molecular Profiling of HR+/HER2- Metastatic Breast Cancer Treated With Endocrine Therapy and Ribociclib.

Conditions
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Advanced or Metastatic Breast Cancer (BC)

Intervention / Treatment
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* Genetic: Pre-treatment biopsy
* Genetic: Post treatment biopsy
* Genetic: Pre treatment blood sampling
* Genetic: Post treatment blood sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients included in the RosaLEE study. Patients having read and signed the ICF relative to Trans-RosaLEE. Tumour material: primary and/or metastatic tumour sample, either available as frozen and collected within 3 months before V0, or newly collected before ribociclib + ET treatment initiation. Brain metastases and non-osteolytic bone metastases will be considered as non-collectable/biopsable. Patient affiliated to the national Social Security regimen or beneficiary of this regimen. Exclusion Criteria: Not enrolled in RosaLEE. Brain metastasis and non-osteolytic bone metastases as only metastatic sites, if no available frozen tumour sample already collected within 3 months before V0. Tumour material not collected before ribociclib + ET initiation. Person subject to a legal protection measure (adult under guardianship, curatorship or safeguard of justice), or unable to give their consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Locally advanced or metastatic Breast Cancer Women<br>Study Procedures: Additional tumour sampling during the pre-treatment biopsy scheduled as per routine care, A post-treatment tumour biopsy, One pre-treatment and one post-treatment blood sampling. | Genetic: Pre-treatment biopsy<br>* Pre-treatment fragments will be collected during the biopsy visit organised as part of routine medical practice, prior to the start of treatment with ribociclib + ET<br>Genetic: Post treatment biopsy<br>* Post-treatment fragments will be collected during a biopsy visit specifically planned for Trans-RosaLEE study.<br>Genetic: Pre treatment blood sampling<br>* Sampling of 4 EDTA Tubes (4ml) and 2 Streck tubes (10ml)<br>Genetic: Post treatment blood sampling<br>* Sampling of 2 Streck tubes (10ml)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular alterations post- versus pre-treatment | Occurrence of molecular alterations, including DNA copy number, gene mutations by WES and messenger RNA (mRNA) expression profiles by RNA-seq in paired post- versus pre-treatment samples. | At the date of first documented progression, assessed up to 54 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular alterations associated with progression free survival | Occurrence of molecular alterations in pre-treatment samples, such as DNA copy number alterations and mutational profiles analysed by WES, and mRNA expression profiles analysed by RNA-seq, associated with progression free survival. | At 3 years after treatment initiation (Ribociclib+hormone therapy) | 
| Molecular alterations pre and post-treatment | Occurrence of molecular alterations, including DNA copy number, gene mutations by WES and mRNA expression profiles by RNA-seq in the totality of pre- and post-treatment samples (paired and unpaired). | At the date of first documented progression, assessed up to 54 months | 
| Pre treatment molecular alterations associated with tumor response | Occurrence of molecular alterations in pre-treatment samples, such as DNA copy number alterations and mutational profiles analysed by WES and mRNA expression profiles analysed by RNA-seq, associated with tumour response according to RECIST 1.1 guidelines (complete and partial responses). | At 3 years after treatment initiation (Ribociclib+hormone therapy) | 
| Molecular alterations therapeutically actionable | Occurrence of molecular alterations in pre- and post-treatment samples, such as DNA copy number alterations and mutational profiles analysed by WES, which are therapeutically actionable according to the ESCAT scale. | At the date of first documented progression, assessed up to 54 months | 
| Percentage of patients with molecular alterations therapeutically actionable | Percentage of patients with molecular alterations such as DNA mutations and/or copy number alterations by WES, which are therapeutically actionable according to the ESCAT scale, in pre- and post-treatment samples. | Through study completion, an average of 54 months | 
| Percentage of patients with modification of the therapeutic strategy derived from the molecular profiling | Percentage of patients for which modification of the therapeutic strategy could have been derived from the molecular profiling of the post-treatment samples compared to that of the pre-treatment samples, according to the ESCAT scale. | Through study completion, an average of 54 months | 
| IHC profile ER | IHC profile ER of pre- and post-treatment samples. | At the date of first documented progression, assessed up to 54 months | 
| IHC profile PgR | IHC profile PgR of pre- and post-treatment samples. | At the date of first documented progression, assessed up to 54 months | 
| IHC profile HER2 | IHC profile HER2 of pre- and post-treatment samples. | At the date of first documented progression, assessed up to 54 months | 
| Molecular subtypes PAM50 | Molecular subtypes PAM50 of pre- and post-treatment samples. | At the date of first documented progression, assessed up to 54 months |