Neoadjuvant Study of Targeting ROS1 in Combination With Endocrine Therapy in Invasive Lobular Carcinoma of the Breast (ROSALINE) (ROSALINE)
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|ClinicalTrials.gov Identifier: NCT04551495|
Recruitment Status : Recruiting
First Posted : September 16, 2020
Last Update Posted : July 8, 2021
|Condition or disease||Intervention/treatment||Phase|
|Invasive Lobular Breast Carcinoma ER+ Breast Cancer HER2-negative Breast Cancer||Drug: Entrectinib Drug: Letrozole Drug: Goserelin||Phase 2|
The neoadjuvant setting has been the target of increasing interest recently, as it offers the possibility of direct evaluation of treatment effect on tumour size, better surgical results as well as for the possible research opportunities it provides via the comparative analysis of tumour biology and clinical outcomes before and after treatment.
Invasive lobular breast cancer (ILBC) is the second most common histologic subtype (5-15%) after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. Indeed, subjects with ILBC tend to have lower response rates to conventional chemotherapeutic agents and some results have suggested that they might derive increased benefit with aromatase inhibitors.
CDK4/6 inhibitors in combination with endocrine therapy are FDA-approved for the treatment of ER-positive/HER2-negative metastatic breast cancer following the results of 7 positive phase 3 trials. These agents are currently tested in phase 3 studies in the adjuvant setting and might achieve the status of standard of care for subjects with ER-positive/HER2-negative early breast cancer treated with curative intent. In the NeoPAL (UCBG10/4, NCT02400567) neoadjuvant randomized study, Residual Cancer Burden (RCB) 0-1 status was achieved for 7.7% of subjects in the letrozole + palbociclib arm. This rate is not available for the 7 subjects with lobular breast cancer enrolled in this arm.
In lobular breast cancer, loss of E-cadherin (CDH1) expression is the most frequent oncogenic event and is present in 90% of cases. In vitro, ex vivo, and in vivo model systems as well as different functional profiling modalities (genetic and chemical screens) have been used to identify CDH1 synthetic lethality interactions. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer, providing the preclinical rationale for assessing ROS1 inhibitors in this setting. A study is currently investigating this hypothesis in ER+/HER2- metastatic lobular breast cancer (NCT03620643).
Entrectinib is a potent small-molecule tyrosine kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1, and ALK. In vitro, entrectinib potently ROS1 at low nanomolar concentrations, with an average median inhibitory concentration of 0.007 μM against ROS1.
This single arm, multi-center, phase 2 trial will include pre and post-menopausal women with ER-positive/HER2-negative early stage invasive lobular carcinoma of the breast to evaluate the effect of combining endocrine therapy with entrectinib. Subjects will receive four 28-day cycles of letrozole 2.5 mg daily in combination with entrectinib 600 mg daily. Pre-menopausal women will receive goserelin 3.6 mg every 28 days.
Subjects' response to therapy will be evaluated at screening, after 2 cycles and after the 4 cycles of treatment by breast magnetic resonance imaging (MRI). An ECG will be performed at screening and then before cycle 2. Surgery will take place after at least 16 weeks of treatment, during week 18 (+ 7-day window). Breast and axillary surgery will follow local practice.
Post-operative therapy will be at the discretion of the investigator and will follow local practice.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Single arm, muti-center, phase 2 trial|
|Masking:||None (Open Label)|
|Official Title:||Neoadjuvant Study of Targeting ROS1 in Combination With Endocrine Therapy in Invasive Lobular Carcinoma of the Breast|
|Actual Study Start Date :||January 14, 2021|
|Estimated Primary Completion Date :||October 2022|
|Estimated Study Completion Date :||March 2023|
Experimental: Single Arm
Subjects will receive four 28-day cycles of letrozole 2.5 mg daily in combination with entrectinib 600 mg daily. Pre-menopausal women will receive goserelin 3.6 mg every 28 days.
Entrectinib is administered orally at a dose of 600 mg once a day from days 1 to 28 of a 28-day cycle for four cycles
Letrozole is administered orally at a dose of 2.5 mg once a day from days 1 to day 28 of a 28 day cycle for four cycles
Goserelin is administered subcutaneously at a dose of 3.6 mg at the beginning of each cycle for 4 monthly cycles to pre-menopausal women
- Evaluation of the efficacy of endocrine therapy + entrectinib in women with ER+/HER2- early breast cancer of the lobular subtype:Residual Cancer Burden (RCB) [ Time Frame: At surgery ]Residual Cancer Burden (RCB) 0/1 by local evaluation in all enrolled subjects.
- Evaluation of the efficacy of the combination by pathology: Pathologic complete response (pCR) rate [ Time Frame: At surgery ]Pathologic complete response (pCR) rate in breast and axilla (ypT0/Tis ypN0) by local evaluation
- Evaluation the efficacy of the combination by imaging: Tumour objective response [ Time Frame: At surgery ]Tumour objective response assessed by locally-assessed breast MRI via modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1.)
- Evaluation of the safety of endocrine therapy + entrectinib: adverse events [ Time Frame: Up to 5 months ]Incidence, nature, and severity of adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0).
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): NCT04551495
|Contact: Philippe Aftimos, MD||+32 2 541 email@example.com|
|Contact: Diane Delaroche, PhD||+32 2 541 firstname.lastname@example.org|
|Brussels, Belgium, 1090|
|Contact: Alex De Waele email@example.com|
|Principal Investigator: Christel Fontaine, MD|
|Brussels, Belgium, 1200|
|Contact: Nathalie Blondeel firstname.lastname@example.org|
|Principal Investigator: François Duhoux, MD|
|Institut Jules Bordet||Recruiting|
|Bruxelles, Belgium, 1000|
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|Grand Hôpital de Charleroi||Recruiting|
|Charleroi, Belgium, 6000|
|Contact: Stéphanie Adam firstname.lastname@example.org|
|Principal Investigator: Jean-Luc Canon, MD|
|Gent, Belgium, 9000|
|Contact: Lore Vansteelant email@example.com|
|Principal Investigator: Hannelore Denys, MD|
|CHU Namur - Sainte Elisabeth||Recruiting|
|Namur, Belgium, 5000|
|Contact: Chloé Charloteaux firstname.lastname@example.org|
|Principal Investigator: Donatienne Taylor, MD|
|Bordeaux, France, 33076|
|Contact: Leslie Ardilouze L.Ardilouze@bordeaux.unicancer.fr|
|Principal Investigator: Camille Chakiba, MD|
|Paris, France, 75248|
|Contact: Anne Blondel email@example.com|
|Principal Investigator: Florence Coussy, MD|
|Institut Gustave Roussy||Recruiting|
|Villejuif, France, 94805|
|Contact: Johanne Poty Johanne.POTY@gustaveroussy.fr|
|Principal Investigator: Barbara Pistilli, MD|
|Study Chair:||Philippe Aftimos, MD||Jules Bordet Insitute|