| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hormone receptor (HR) positive / HER2-negative localized breast cancer in menopausal patient considered as having an intermediate risk of relapse. |
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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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to show that a combination of letrozole + palbociclib, in the absence of chemotherapy, allows high invasive Disease-free survival (iDFS) in intermediate clinico-pathological risk, HR positive / HER2-negative localized breast cancer patients.. |
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| E.2.2 | Secondary objectives of the trial |
• To determine patient quality of Life (QoL) in term of:
o General QoL
o Fatigue
o Psychological
o Cognitive functions
• To determine the treatment efficacy in term of:
o Metastasis free survival (MFS)
o Metastasis free survival rate by stade (pT1-T2, pN0-N1)
o iDFS in Luminal A and Luminal B subtypes
o Loco regional recurrences-free (LRRFS) survival
o Overall Survival (OS)
• To determine the safety of the treatment in term of:
o Short and long-term toxicities
• Adherence with study treatment
Exploratory objective:
•To correlate the toxicity and iDFS to germ line polymorphisms. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
APOLON CNS (version 1.0, 2 April 2020)
Objective: •To determine cognive impact in a subset of patients.
Endpoint:
•Cognive impact in collaboration with Cancer&Cognition platform (www.canceretcognition.fr) located in Caen (France) at baseline, 12 and 36-month post-study entry time point:
–Objective cognitive functions will be focused on processing speed, attention, working memory and short term memory (the main cognitive domains that could be impacted) and will be assessed by a web-battery of 7 neuropsychological tests: Finger Tapping (FTT); Continuous Performance (CPT); Shifting Attention (SAT); Symbol Digit Coding (SDC); Stroop Test (ST); Verbal Memory (VBM); Visual Memory (VIM). The tests are on the CNS website: https://www.cnsvs.com/ (central nervous system vital signs [CNSVS]).
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| E.3 | Principal inclusion criteria |
1.Female, age ≥18 years
2.Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
3.Histologically confirmed adenocarcinoma of the breast (bilateral breast cancer allowed)
4.Breast cancer tumor removed by surgery
5.Hormone receptor positive: ER+ and/or PR+ by IHC (≥10%)
6.HER2-negative by IHC (score 0 or 1+) and/or DISH negative (HER2 copy number <6 and HER2/CEP17 ratio <2)
7.Intermediate risk breast cancer defined by pathological characteristics as follow:
-pT1 AND pN0* AND histological grade 3
-or pT1 AND pN1 AND histological grade 1 or 2
-or pT2 AND pN0* AND histological grade 2
* pN1a or pNmi reflecting the presence of micrometastases and pN0(i+) representing isolated tumour cells will be classified as pN0
Note: In case a genomic test has been performed and the result classifies the patient in an intermediate risk, patient is eligible independently of the pathological characteristics listed above.
8.No prior pre-operative or (neo)adjuvant/adjuvant chemotherapy, targeted therapy or endocrine therapy. Short term, window of opportunity preoperative therapy, will be allowed provided cancer biology is assessed on the primary biopsy.
9.Postmenopausal women, as defined by any of the following criteria:
-Prior bilateral oophorectomy
-Age ≥60 years
-Age <60 years and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and FSH and estradiol in the postmenopausal range
10.Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria:
-Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L
-Platelets ≥100,000/mm3 or ≥100 x 109/L
-Hemoglobin ≥9 g/dL
-Serum Aspartate Transaminase (AST) and serum Alanine Aminotransferase Transaminase (ALT) ≤2.5 x upper limit of normal (ULN) (4x if liver metastasis)
-Alkaline phosphatase ≤2.5 x ULN
-Total serum creatinine ≤1.5 x ULN or estimated creatinine clearance >60 mL/min as calculated using the method standard for the institution
11.Adequate cardiac functions, including:
-12 Lead electrocardiograms (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention.
-QTc interval ≤480 msec (mean of replicate values, correction per institutional standard)
-No history of Torsades de Pointes or other symptomatic QTc abnormality.
12.Patient must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures.
13.Patient must have signed a written informed consent prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent.
14.Patient must be affiliated to a Social Security System (or equivalent). |
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| E.4 | Principal exclusion criteria |
1.pN2 or pN3 (>3 involved nodes)
2.pT3 or c/pT4
3.Metastatic disease (M1)
4.Multifocal tumors with >3 invasive lesions (in case of multifocal lesions up to 3, all must share the same biological profile)
5.Hormone Receptor or HER2 unknown disease
6.Prior pre-operative or (neo)/adjuvant/adjuvant chemotherapy, targeted therapy or endocrine therapy (except short term window of opportunity therapy as described in inclusion criteria)
7.Patients who have not recovered from the side effects of any major surgery
8.Inability or willingness to swallow oral medication
9.Previous treatment with palbociclib or any other CDK 4/6 inhibitors
10.Contraindications or known hypersensitivity to letrozole, palbociclib or any of their excipients
11.History of mal-absorption syndrome or other condition that would interfere with enteral absorption
12.Patients receiving any drug that is known to be potent inhibitor or inducer of CYP3A isoenzymes within the last 7 days prior to treatment start in the trial
13.Patients with a history of malignancy, other than invasive breast cancer, with the following exceptions:
-Patients diagnosed, treated and disease-free for at least 5 years and deemed by the investigator to be at low risk for recurrence of that malignancy are eligible
-Patients with the following malignancies are eligible, even if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast; cervical cancer in situ; thyroid cancer in situ; non-metastatic, non-melanomatous skin cancer.
14.Concurrent disease or condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient’s safety, such as:
-Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen, etc.
-Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification. To be eligible for this trial, patients should be class 2B or better.
-Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial.
-For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
-Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
15.Patients with psychiatric illness/social situations that would limit adherence with study requirements.
16.Participation in another therapeutic trial within the 30 days prior to initiation of treatment.
17.Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons.
18.Persons deprived of their liberty or under protective custody or guardianship
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Invasive disease free survival (iDFS) is defined as duration of time from date of registration until first appearance of invasive local, regional, or distant recurrence (including invasive ipsilateral breast cancer recurrence), invasive contralateral breast cancer, second primary non breast invasive cancer (excluding non-melanoma skin cancer), or death from any cause. |
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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) |
•Patient-related outcomes at baseline, 12 and 36-month post-study entry time point:
–QoL (EORTC QLQ-C30, EORTC QLQ-BR23 or EORTC QLQ-BR45),
–Fatigue (EORTC QLQ-FA12),
–Psychological (HADS Anxiety and HADS Depression),
–Cognitive complaints will be assessed by a validated self-reported Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) version 3.
•Efficacy:
–Metastasis free survival (MFS) defined as the time interval between the date of registration in the study and the date of the occurrence of distant metastasis (including liver and non-liver metastases) or death (all causes), whichever occurs first.
–MFS rate by stade (pT1-T2, pN0-N1)
–iDFS in Luminal A and Luminal B subtypes
–Loco-regional relapse-free survival (LRFS) defined as the time interval between the date of registration in the study and the date of local relapse or regional relapse or death (all cause) whichever occurs first.
–Overall Survival (OS) defined as the time interval between the date of registration in the study and the date of death (all causes)
•Safety:
–Short and long-term Adverse Events will be graded according to NCI-CTCAE v5.0
•Adherence with study treatment:
–Daily self-recording data in a diary using the mobile application developed by Betterise.
Exploratory endpoint:
•Biological:
–Genetic variant analysis will use genome wide chips designed to capture common variation across the genome
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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 | 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 | 45 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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