Neoadjuvant Treatment of Locally-advanced Breast Cancer Patients With Ribociclib and Letrozole (NEOLETRIB)
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|ClinicalTrials.gov Identifier: NCT05163106|
Recruitment Status : Not yet recruiting
First Posted : December 20, 2021
Last Update Posted : July 22, 2022
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer HER2-negative Breast Cancer ER-positive Breast Cancer Locally Advanced Breast Cancer Luminal A Breast Cancer Luminal B Breast Cancer||Drug: Letrozole 2.5mg oral tablet; Ribociclib 600mg oral tablet Drug: Goserelin||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Multicentre, single-arm, open-label, neoadjuvant study model|
|Masking:||None (Open Label)|
|Official Title:||Presurgical Treatment With Ribociclib and Letrozole in Patients With Locally Advanced Breast Cancer: the NEOLETRIB Study.|
|Estimated Study Start Date :||December 1, 2022|
|Estimated Primary Completion Date :||December 1, 2023|
|Estimated Study Completion Date :||December 1, 2024|
Experimental: Ribociclib and Letrozole Arm
Patients entered into this study will be given letrozole (FemarTM) in combination with ribociclib (KisqaliTM) for at least 6 months. Premenopausal women will also receive treatment with goserelin 3.6 mg s.c. every 4 weeks.
Drug: Letrozole 2.5mg oral tablet; Ribociclib 600mg oral tablet
Patients will be given letrozole 2.5mg and ribociclib 600mg daily, per oral for a period of 21 days followed by 7 days of letrozole only.
Other Name: Femara; Kisqali
Premenopausal women will be given goserelin 3.6 mg (subcutaneous) every 4 weeks in concert with their Letrozole and Ribociclib treatment.
Other Name: Zoladex
- To study the change in levels of direct and indirect immunologic biomarkers of targeted cancer therapy with letrozole and ribociclib given in combination for patients with locally-advanced, ER-positive, HER-2 negative, luminal A7B breast cancer [ Time Frame: Baseline, Day 21 and at time of surgery (Day 180) ]In order to accurately profile changes in the composition of the tumor over time and identify potentially-related biomarkers of response within the tumor, single cell RNA panels will be performed at three points during the treatment period. Samples of tumor tissue will be obtained, and the cells dissociated at the single cell level. These dissociated cells will then be subjected to RNA profiling via scRNA-seq. Genes expressed at a rate higher than the threshhold (generally 50 reads per kb per million reads) will be examined using t-Distributed Stochastic Neighbor Embedding, (tSNE) clustering, generally shown as a scatterplot, to allow the characterisation of phenotypes (clones). Using this technique, it will be evident which tumour phenotypes are eradicated by the treatment combination and which are not. This examination will also help to monitor patient response.
- Measurement of changes in the tumor through DNA profiling throughout the treatment cycle with letrozole and ribociclib [ Time Frame: Baseline, Day 21 and at time of surgery (Day 180) ]In order to examine the potential genetic changes within the tumor during treatment, samples of tumor tissue will be taken and examined using standard DNA profiling. Baseline samples will be compared to those at day 21 and at the time of surgery (6 months). This outcome will allow identification of overall tumour composition and changes to over the course of the therapy.
- Confirmation of the breast cancer subtype [ Time Frame: Baseline ]To determine the subtypes of the tumor, a PROSIGNA-test will be undertaken on all samples to confirm their subtype.
- Changes in neoantigens and single T-cell receptor function after treatment with letrozole and ribociclib [ Time Frame: Baseline, Day 21 and at time of surgery (Day 180) ]In order to examine the effects of letrozole and ribociclib on the presence of immune cells within the tumor throughout treatment, samples of tumor tissue will be extracted and cells will be dissociated at the single-cell level using enzymatic and mechanical means. Measurement of tumor neoantigens and testing of the ability of the T-cell receptors to recognise these neoantigens will assist in the understanding of the "rules" and molecular events underlying immune-mediated tumor destruction. Further, responders and non-responders will be compared to identify whether they belong to a new yet undiscovered subtype.
- Determination of the histopathological sub-type and status of the tumour [ Time Frame: Baseline, Day 21 and at time of surgery (Day 180) ]To ensure the correct patients are identified for participation in this study, and to record overall baseline information, samples of tumor tissue will be examined via standard histopathological investigations including subtyping, grading, ER-status, PGR-status, HER-2 status and level of Ki67-expression will be undertaken by a qualified pathologist. After the baseline, examination will confirm that biopsies consist of tumor tissue.
- Determination of the early and late mechanisms of adaptation and/or resistance to letrozole in combination with ribociclib [ Time Frame: Baseline and at time of surgery (Day 180) ]Using single-cell RNA-seq (scRNA-seq), thousands of individual cells will be profiled to build a cellular atlas of whole tumor biomarkers for targeted cancer treatments. scRNA-seq allows the characterisation of phenotypes (clones) to assist in determination of the phenotypes eradicated by the treatment, and to find biomarkers of response. Further knowledge of the phenotypes of the cells most affected by the therapy may assist in the identification of further drugs targeting any cells that remain or thrive.
- Change in PEPI status from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib [ Time Frame: Baseline, Day 21, Day 90, Day 180 ]Preoperative endocrine prognostic index (PEPI) status will be evaluated across the treatment period using the procedure outlined in Ellis et al, 2008.
- Change in Ki67 from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib [ Time Frame: Baseline, Day 21, Day 90, Day 180 ]Levels of Ki67 will be evaluated across the study period using the XXXXX protocol. Complete Cell Cycle Arrest (CCCA) will be recorded as a Ki67 of less than 2.7%.
- Change in PROSIGNA Risk of Recurrence (ROR) score from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib [ Time Frame: Baseline, Day 21, Day 90, Day 180 ]
- Changes in the composition of the gut microbiota [ Time Frame: Baseline, 21 and 90, at time of surgery (Day 180), and annually in years 1-5 (extension if patient relapses) ]A DNA-based approach to determination of fecal microbial composition will be performed. Stool samples will be collected at baseline, and during follow ups at day 21, day 90 and at time of surgery (day 180), and thereafter annually in years 1-5 (further if patient relapses). DNA purification from fecal samples will be performed using PSP Spin Stool DNA Plus Kit (Stratec Molecular GMBH). Next generation amplicon sequencing targeting the V4 region of the 16S rRNA gene (DNA) will be applied to detect the members of the fecal microbiota.
- Identification of anti-tumor effects via changes in levels of circulating serum cytokines in liquid biopsies [ Time Frame: Baseline, 21 and 90, and at time of surgery (Day 180). ]Serum cytokines will be measured using 54-plex cytokine panel, and analyzed with Luminex xMAP 200. The assay includes a series of known concentrations giving standard curves. Samples will be analyzed in duplicate.
- Identification of anti-tumor effects via changes in levels of circulating serum metabolites in liquid biopsies [ Time Frame: Baseline, 21 and 90, and at time of surgery (Day 180). ]Circulating metabolites will be identified using high resolution magic angle spinning mass spectrometry as described in Bathen et al (2013).
- Identification of anti-tumor effects via circulating free tumor DNA (cftDNA) in liquid biopsies [ Time Frame: Baseline, 21 and 90, and at time of surgery (Day 180). ]Circulating free tumor DNA will be collected and identified using standard DNA extraction and analysis techniques.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05163106
|Contact: Jürgen Geisler, MD, PhD||+47 email@example.com|
|Contact: Thale D JH Patrick-Brown, MSc||+47 firstname.lastname@example.org|
|Akershus University Hospital|
|Lørenskog, Viken, Norway, 1478|
|Contact: Jürgen Geisler, MD, PhD +47 91187447 email@example.com|
|Contact: Thale D JH Patrick-Brown, MSc +47 94866958 firstname.lastname@example.org|
|Principal Investigator: Jürgen Geisler, MD, PhD|
|Principal Investigator:||Jürgen Geisler, MD, PhD||University Hospital, Akershus|