| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ER-positive/HER2-negative invasive lobular carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
| ER-positive/HER2-negative invasive lobular carcinoma |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073096 |
| E.1.2 | Term | Invasive lobular breast carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of endocrine therapy + entrectinib in women with ER-positive/HER2-negative early breast cancer of the lobular subtype |
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| E.2.2 | Secondary objectives of the trial |
To further evaluate the efficacy of the combination by pathology.
To further evaluate the efficacy of the combination by imaging.
To evaluate the safety of endocrine therapy + entrectinib.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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-.
o ER positive (ER+ is defined as having an IHC of 1% or more and/or an Allred of 3 or more and HER2-).
o 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 more than 20 mm as measured by breast MRI, cN0 or cN1 without prior treatment candidate for preoperative treatment.
6. ECOG Performance Status (PS) 0 or 1.
7. Adequate Bone Marrow Function including:
o Absolute Neutrophil Count (ANC) ≥1500/μL or ≥1.5x109/L;
o Platelets ≥100000/μL or ≥100 x 109/L;
o 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:
o Total serum bilirubin ≤ 2.0 x ULN unless the subject has documented Gilbert syndrome
o 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.
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| E.4 | Principal exclusion criteria |
Subjects who exhibit any of the following conditions at screening will not be eligible for admission into the study.
1. Clinical T4 disease including inflammatory breast cancer and/or cN2 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).
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 (ECHO should be the preferred method)
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); uncorrected electrolyte imbalances
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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| RCB 0/1 by local evaluation in all enrolled subjects. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Pathologic complete response (pCR) rate in breast and axilla (ypT0/Tis ypN0) by local evaluation.
Tumour objective response assessed by locally-assessed breast MRI via modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1.).
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).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of trial is declared when all the following criteria have been met:
- After last visit of the last subject (one month after the surgery day of the last subject)
- The database has been fully cleaned and frozen for the final analysis
- All endpoints (with the exception of translational research endpoints) have been analysed
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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