Neoadjuvant Study of Targeting ROS1 in Combination With Endocrine Therapy in Invasive Lobular Carcinoma of the Breast (ROSALINE) (ROSALINE)

April 14, 2023 updated by: Jules Bordet Institute

Neoadjuvant Study of Targeting ROS1 in Combination With Endocrine Therapy in Invasive Lobular Carcinoma of the Breast

Despite different clinical characteristics including the response to treatment and the patterns of metastatic relapse, invasive lobular breast carcinoma (ILBC) is treated like invasive ductal breast carcinoma (IDBC) carcinoma both in the clinics and in clinical trials. A large majority of ILBC are ER+/HER2- and almost 90% have loss of E-cadherin (CDH1) expression. A non-clinical study of CDH1 synthetic lethality interactions has identified ROS1 as a potential target. 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. Endocrine therapy being the mainstay of therapy for ER+/HER2- ILBC and the pre-operative setting offering a platform for rapid drug evaluation and biomarker research, the ROSALINE phase 2 study will evaluate the efficacy of Entrectinib (a potent inhibitor of ROS1 among other targets) in combination with letrozole (+ goserelin in premenopausal women) in the early setting of ILBC (stages 1 to 3). The neoadjuvant therapy will last 4 months and post-operative therapy will follow local practice. Biomarker research will include RNA sequencing of initial biopsies and surgical specimens, as well as liquid biopsies.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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

Enrollment (Anticipated)

65

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Female
  2. Age ≥ 18 years
  3. Histological diagnosis of invasive lobular breast adenocarcinoma that is ER+, and HER2- as per the updated American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines according to local testing.

  4. Multifocal unilateral or bilateral breast adenocarcinoma tumours are allowed if all tested foci are lobular, ER+ and HER2-.

    • ER positive (ER+ is defined as having an IHC of 1% or more and/or an Allred of 3 or more and HER2-).
    • HER2 negative as defined by 2018 ASCO / CAP Guidelines
  5. A primary non metastatic or locally advanced tumour of 15 mm or more, cN0 or cN1 without prior treatment candidate for preoperative treatment.
  6. ECOG Performance Status (PS) 0 or 1.

  7. Adequate Bone Marrow Function including:

    • Absolute Neutrophil Count (ANC) ≥1500/μL or ≥1.5x109/L;
    • Platelets ≥100000/μL or ≥100 x 109/L;
    • Haemoglobin ≥ 9 g/dL.

  8. Adequate Renal Function including:

    o Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 60 ml/min as calculated using the method standard for the institution.

  9. Adequate Liver Function, including all of the following parameters:

    • Total serum bilirubin ≤ 2.0 x ULN unless the subject has documented Gilbert syndrome
    • Aspartate and Alanine Aminotransferase (AST and ALT) ≤ 3 x ULN;
  10. Signed Informed Consent form (ICF) obtained prior to any study related procedure.
  11. Completion of all necessary screening procedures within 28 days prior to enrolment. Biopsies at screening must have been obtained up to max 6 weeks before the beginning of treatment.
  12. Subject is willing and able to comply with the protocol for the duration of the study including treatment and scheduled visits and examinations.
  13. Women who are not postmenopausal or have not undergone hysterectomy must have documented negative pregnancy test (serum) within 28 days prior to enrolment.

  14. Women of childbearing potential and their partners, who are sexually active, must agree to use one highly effective form of contraception (see protocol section 6.6.1) from the signing of the ICF until at least 5 weeks after last administration of entrectinib, or they must totally/truly abstain from any form of sexual intercourse. Use of oral hormonal contraceptive agents in this study is not permitted.

    Inclusion criterion applicable to FRANCE only:

  15. Subject is affiliated to the French Social Security System.

Exclusion Criteria:

  1. Clinical T4 disease including inflammatory breast cancer and/or cN3.
  2. Prior history of invasive cancer in the past 5 years except basal or squamous cell carcinoma of skin that has been definitively treated.
  3. Known hypersensitivity to the study drugs or excipients.
  4. Hyperuricemia > Grade 1
  5. Any illness or medical condition that is unstable or could jeopardize the safety of the subject or her compliance with study requirements.
  6. Subjects unable to swallow oral medications.
  7. Prior intake of letrozole, any ROS1 inhibitor, any TRK inhibitor or anticancer therapy (including endocrine therapy). Ovarian suppression including prior administration of a LHRH analogue (i.e. goserelin) is allowed prior to cycle 1 day 1, at the discretion of the investigator.
  8. Concurrent treatment with strong or moderate CYP3A inhibitor.
  9. Concurrent treatment with any of the drugs not permitted, i.e. strong CYP3A inducers and drugs known to cause QTc interval prolongation.
  10. Significant cardiac disease, including recent (less than 6 months) myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias.
  11. LVEF ≤ 55% measured by echo or MUGA
  12. QTc exceeding 450 msec, history of prolonged QTc interval prolongation; risk factors for torsade de pointes; other concomitant medications that may prolong QTc; family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
  13. Pregnant or lactating women.
  14. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
  15. Peripheral neuropathy ≥ Grade 2

  16. Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.

    Exclusion criterion applicable to France only

  17. Vulnerable persons according to the article L.1121-6 of the CSP, adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the CSP.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Drug: Entrectinib
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
Drug: Letrozole
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
Drug: Goserelin
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
At surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
At surgery

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.)
At surgery
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).
Up to 5 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Jules Bordet Institute

Collaborators

Hoffmann-La Roche

Investigators

  • Study Chair: Philippe Aftimos, MD, Jules Bordet Insitute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 14, 2021

Primary Completion (Anticipated)

April 1, 2024

Study Completion (Anticipated)

July 1, 2024

Study Registration Dates

First Submitted

September 9, 2020

First Submitted That Met QC Criteria

September 15, 2020

First Posted (Actual)

September 16, 2020

Study Record Updates

Last Update Posted (Actual)

April 18, 2023

Last Update Submitted That Met QC Criteria

April 14, 2023

Last Verified

October 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IJB-LOB-2019

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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