Clinical Trials /

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

NCT04551495

Description:

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 biopsis and surgical specimens, as well as liquid biopsies.

Related Conditions:
  • Breast Invasive Lobular Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Study of Targeting ROS1 in Combination With Endocrine Therapy in Invasive Lobular Carcinoma of the Breast (ROSALINE)
  • Official Title: Neoadjuvant Study of Targeting ROS1 in Combination With Endocrine Therapy in Invasive Lobular Carcinoma of the Breast

Clinical Trial IDs

  • ORG STUDY ID: IJB-LOB-2019
  • NCT ID: NCT04551495

Conditions

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

Interventions

DrugSynonymsArms
EntrectinibSingle Arm
LetrozoleSingle Arm
GoserelinSingle Arm

Purpose

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 biopsis and surgical specimens, as well as liquid biopsies.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Single ArmExperimentalSubjects 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
  • Letrozole
  • Goserelin

Eligibility Criteria

        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 (HER2- is defined as having an IHC of 0 or 1+ without ISH OR IHC 2+
                  and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy
                  number < 4 signals/cells OR ISH non-amplified with ratio less than 2.0 and if
                  reported, average HER2 copy number < 4 signals/cells [without IHC]);

          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. Any illness or medical condition that is unstable or could jeopardize the safety of
             the subject or her compliance with study requirements.

          5. Subjects unable to swallow oral medications.

          6. Prior intake of letrozole, any ROS1 inhibitor, any TRK inhibitor or anticancer therapy
             (including endocrine therapy).

          7. Concurrent treatment with strong or moderate CYP3A inhibitor.

          8. Concurrent treatment with any of the drugs not permitted, i.e. strong CYP3A inducers
             and drugs known to cause QTc interval prolongation.

          9. LVEF ≤ 55% measured by echo or MUGA

         10. 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).

         11. Pregnant or lactating women.

         12. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase
             inhibitor-induced pneumonitis

         13. Peripheral neuropathy ≥ Grade 2

         14. 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 14. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Residual Cancer Burden (RCB) 0/1 by local evaluation in all enrolled subjects.

Secondary Outcome Measures

Measure:Evaluation of the efficacy of the combination by pathology: Pathologic complete response (pCR) rate
Time Frame:At surgery
Safety Issue:
Description:Pathologic complete response (pCR) rate in breast and axilla (ypT0/Tis ypN0) by local evaluation

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jules Bordet Institute

Last Updated

September 15, 2020