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

NCT04551495 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: IJB-LOB-2019
• Study Type: interventional
• Target: 65
• Locations: 2 countries
• Sites: 10

Brief Summary

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.

Conditions

Invasive Lobular Breast Carcinoma; ER+ Breast Cancer; HER2-negative Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Evaluation of the efficacy of endocrine therapy + entrectinib in women with ER+/HER2- early breast cancer of the lobular subtype:Residual Cancer Burden (RCB)

  Residual Cancer Burden (RCB) 0/1 by local evaluation in all enrolled subjects.

  At surgery

Secondary Outcomes (1)

• Evaluation of the efficacy of the combination by pathology: Pathologic complete response (pCR) rate

  At surgery

Other Outcomes (2)

• Evaluation the efficacy of the combination by imaging: Tumour objective response

  At surgery

• Evaluation of the safety of endocrine therapy + entrectinib: adverse events

  Up to 5 months

Study Arms (1)

Single Arm

EXPERIMENTAL

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; Drug: Letrozole; Drug: Goserelin

Interventions

Entrectinib DRUG

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

Single Arm

Letrozole DRUG

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

Single Arm

Goserelin DRUG

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

Single Arm

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female
• Age ≥ 18 years
• 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.
• 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
• A primary non metastatic or locally advanced tumour of 15 mm or more, cN0 or cN1 without prior treatment candidate for preoperative treatment.
• ECOG Performance Status (PS) 0 or 1.
• 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.
• 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.
• Adequate Liver Function, including all of the following parameters:

You may not qualify if:

• Clinical T4 disease including inflammatory breast cancer and/or cN3.
• Prior history of invasive cancer in the past 5 years except basal or squamous cell carcinoma of skin that has been definitively treated.
• Known hypersensitivity to the study drugs or excipients.
• Hyperuricemia \> Grade 1
• Any illness or medical condition that is unstable or could jeopardize the safety of the subject or her compliance with study requirements.
• Subjects unable to swallow oral medications.
• 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.
• Concurrent treatment with strong or moderate CYP3A inhibitor.
• Concurrent treatment with any of the drugs not permitted, i.e. strong CYP3A inducers and drugs known to cause QTc interval prolongation.
• Significant cardiac disease, including recent (less than 6 months) myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias.
• LVEF ≤ 55% measured by echo or MUGA
• 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).
• Pregnant or lactating women.
• Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
• Peripheral neuropathy ≥ Grade 2

Sponsors & Collaborators

• Jules Bordet Institute: lead
• Hoffmann-La Roche: collaborator

Study Sites (10)

Institut Jules Bordet

Brussels, 1070, Belgium

Location

UZ Brussel

Brussels, 1090, Belgium

Location

UCL Saint-Luc

Brussels, 1200, Belgium

Location

Grand Hôpital de Charleroi

Charleroi, 6000, Belgium

Location

UZ Gent

Ghent, 9000, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

CHU Namur - Sainte Elisabeth

Namur, 5000, Belgium

Location

Institut Bergonié

Bordeaux, 33076, France

Location

Institut Curie

Paris, 75248, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Related Publications (2)

• Agostinetto E, Nader-Marta G, Paesmans M, Ameye L, Veys I, Buisseret L, Neven P, Taylor D, Fontaine C, Duhoux FP, Canon JL, Denys H, Coussy F, Chakiba C, Ribeiro JM, Piccart M, Desmedt C, Ignatiadis M, Aftimos P. ROSALINE: a phase II, neoadjuvant study targeting ROS1 in combination with endocrine therapy in invasive lobular carcinoma of the breast. Future Oncol. 2022 Jul;18(22):2383-2392. doi: 10.2217/fon-2022-0358. Epub 2022 Jun 13.

  PMID: 35695563 DERIVED

• Okines A, Irfan T, Asare B, Mohammed K, Osin P, Nerurkar A, Smith IE, Parton M, Ring A, Johnston S, Turner NC. Clinical outcomes in patients with triple negative or HER2 positive lobular breast cancer: a single institution experience. Breast Cancer Res Treat. 2022 Apr;192(3):563-571. doi: 10.1007/s10549-021-06432-z. Epub 2022 Feb 4.

  PMID: 35119530 DERIVED

MeSH Terms

Conditions

Carcinoma, Lobular

Interventions

entrectinib; Letrozole; Goserelin

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Ductal, Lobular, and Medullary; Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Philippe Aftimos, MD

  Jules Bordet Insitute

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single arm, muti-center, phase 2 trial

Study Record Dates

• First Submitted: September 9, 2020
• First Posted: September 16, 2020
• Study Start: January 14, 2021
• Primary Completion: January 1, 2025
• Study Completion: January 1, 2025
• Last Updated: December 4, 2024

Record last verified: 2024-04

Locations

FR (3); BE (7)