| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | LLT |
| E.1.2 | Classification code | 10006192 |
| E.1.2 | Term | Breast cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
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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 identify biomarkers of resistance to a 4-month preoperative treatment of palbociclib plus endocrine therapy defined as stable or progressive disease by ultrasound (based on WHO criteria) using RNA-seq of the baseline tumour biopsy. |
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| E.2.2 | Secondary objectives of the trial |
To identify biomarkers of resistance to a 4-month preoperative treatment of endocrine therapy and palbociclib by correlating tumour response by ultrasound (mandatory) or magnetic resonance (optional) imaging (response will be assessed as continuous or categorical variable) with RNA-seq of the baseline tumour biopsy
To identify biomarkers of resistance to a 4-month preoperative treatment defined as residual disease burden, RCB of 3 using RNA-seq of the baseline tumour biopsy
To identify biomarkers of resistance to a 4-month preoperative treatment defined as GGI high by RNA-seq of the leftover tumour at surgery using RNA-seq of the baseline tumour biopsy
To understand mechanisms of resistance to the combination by comparing the transcriptome of tumours at baseline and at surgery using RNA-seq
To determine the effect of a pre-operative treatment on anti-tumour immune response
To determine the effect of a pre-operative treatment on tumour senescence.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria in order to be eligible for this study:
1. Female.
2. Age ≥ 18 years
3. Histological diagnosis of breast adenocarcinoma that is estrogen receptor-positive, and HER2- negative 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 provided that all tested foci are:
- ER-positive (ER+ is defined as having a IHC of 1% or more and/or and Allred of 3 or more and HER2-negative).
- HER2 negative (HER2 negative 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]; note: a IHC of 3+ is always considered HER2 positive, independently of the ISH result.
5. A primary non metastatic or locally advanced tumour of ≥15 mm or more, assessed by ultrasound, N0 or N1 without prior treatment candidate for preoperative treatment
6. ECOG Performance Status (PS) 0 or 1.
7. Adequate Bone Marrow Function including:
a. Absolute Neutrophil Count (ANC) ≥1500/μL or ≥1.5 x109/L;
b. Platelets ≥100000/μL or ≥100 x 109/L;
c. Hemoglobin ≥ 9 g/dL.
8 Adequate Renal Function including: 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:
a. Total serum bilirubin ≤ 1.0 x ULN unless the subject has documented Gilbert syndrome (in which case up to 3 x ULN is acceptable);
b. Aspartate and Alanine Aminotransferase (AST and ALT) ≤ 1.5 x ULN;
c. Alkaline phosphatase ≤ 2.5 x ULN.
10. Signed consent form
11. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests, radiological exams, tumour and blood specimen collection and other procedures.
12. Women who are not postmenopausal or have not undergone hysterectomy must have documented negative pregnancy test (serum) prior to inclusion.
13. Female subjects of child bearing potential and their partners, who are sexually active, must agree to the use of one highly effective non hormonal form of contraception throughout the period of taking study treatment and for at least 90 days after last dose of study drug, 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 meeting one of the following criteria are not eligible for this study:
1. Clinical T4 disease including inflammatory breast cancer.
2. Prior history of invasive cancer including breast cancer except basal or squamous cell carcinoma of skin that has been definitively treated.
3. Known hypersensitivity to the study drug 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, tamoxifen or any CDK inhibitor or anti-cancer therapy.
7. Concurrent treatment with any of the drugs not permitted, i.e. strong CYP3A inhibitors/inducers and drugs known to cause QT interval prolongation; (see section 5.7 for specific instructions).
8. QTc exceeding 480 msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
9. Uncontrolled diabetes, according to investigator’s clinical judgment.
10. Pregnant or lactating women.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Baseline transcriptomic profile of resistance to 4 months of palbociclib and endocrine therapy defined as stable or progressive disease by ultrasound based on WHO criteria |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After the last treatment of the last patient |
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| E.5.2 | Secondary end point(s) |
• Baseline transcriptomic profile of resistance to 4 months of palbociclib and endocrine therapy assessed by ultrasound (mandatory) or magnetic resonance (optional) imaging (response will be assessed as continuous or categorical variable)
• Baseline transcriptomic profile of resistance to 4 months of palbociclib and endocrine therapy, defined as an RCB of 3.
• Baseline transcriptomic profile of resistance to 4 months of palbociclib and endocrine therapy, defined as an GGI high at surgery
• Transcriptomic changes between pre-treatment and post-treatment tumour samples
• Safety
• Plasma ctDNA analysis to monitor response/resistance to pre-operative treatment with endocrine therapy and palbociclib
• Validation of 11-gene expression signature associated with response/resistance to palbociclib and endocrine treatment
• Changes in anti-tumour immune response between pre- and post-treatment tumour samples;
• Changes in tumour senescence between pre- and post-treatment tumour samples.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After the last treatment of the last patient |
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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 | No |
| 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 | Yes |
| 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 | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
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The end of study will be declared when all the following criteria will have been met:
• After last visit of the last subject (one month after the surgery day of the last subject)
• The trial is mature for the analysis of all the endpoints as defined in the protocol, if the trial reaches its endpoints
• The database has been fully cleaned and frozen for all analyses |
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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 | |
| E.8.9.1 | In the Member State concerned months | 52 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 52 |
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