Neoplasms

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Breast Neoplasms

Breast Diseases

Skin Diseases

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Fulvestrant

Exemestane

Letrozole

Estrogens

Palbociclib

Anastrozole

Aromatase Inhibitors

Enzyme Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Protein Kinase Inhibitors

After randomization, the patient will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with an aromatase inhibitor (letrozole, anastrozole or exemestane, according to physician's choice and according their respective summary product characteristics) administered once daily in a continuous scheme.

After randomization, the patient will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with fulvestrant, a selective estrogen receptor down-regulator, 500 mg administered intramuscularly on Days 1, 15, and 29 and once monthly thereafter.

All patients included into the study will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle in combination with an aromatase inhibitor (letrozole, anastrozole or exemestane, according to physician's choice and according their respective summary product characteristics) administered once daily in a continuous scheme

Palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle

Palbociclib 125mg

Letrozole: 2.5 mg once daily on a continuous scheme (tablets, per os) Anastrozole:1 mg once daily on a continuous scheme (tablets , per os) Exemestane: 25 mg once daily on a continuous scheme (tablets, per os)

500 mg by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days)

Fulvestrant Injectable Product

François-Clément BIDARD, MD PhD

Suzette DELALOGE, MD PhD

Anne-Claire HARDY BESSARD, MD

This study is a randomized, open-label, multicentric, phase III trial conducted in patients receiving aromatase inhibitor and palbociclib as first line therapy for estrogen receptor (ER)-positive HER2-negative metastatic breast cancer and which aims to evaluate, at the onset of ESR1 mutations in circulating tumor DNA, the efficacy of a change of the hormone therapy (aromatase inhibitor (AI) changed to fulvestrant) combined to palbociclib, together with the safety of hormone therapy and palbociclib combination in the overall population.

Step 1: 1000 patients screened for circulating blood ESR1 mutation detection at regular intervals will be treated with palbociclib 125 mg once daily for 21 days followed by 7 days off (28-day cycle) + AI (letrozole, anastrozole or exemestane) administered once daily in a continuous scheme until tumor progression (assessed by RECIST) or ESR1 mutation detection

Step 2: Up to 200 Patients with a rising circulating ESR1 mutation and without tumor progression will be randomized (1:1):

* ARM A: no change in therapy until tumor progression (RECIST) or possibility of a cross-over (step 3)
* ARM B: palbociclib 125 mg + fulvestrant 500 mg administered intramuscularly on D1,15 and 29 and once monthly thereafter until tumor progression (RECIST)
* Step 3 (cross over): up to 80 patients who have been randomized in arm A will be offered to be treated by fulvestrant + palbociclib, after having progressed under AI + palbociclib until tumor progression (RECIST) under fulvestrant + palbociclib.

PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection

Randomized, Open Label, Multicentric Phase III Trial to Evaluate the Safety and Efficacy of Palbociclib in Combination With HT Driven by ctDNA ESR1 Mutation Monitoring in ER+, HER2-negative Metastatic Breast Cancer Patients

Global safety of the combination of palbociclib + endocrine therapy in the whole population, with focus on hematological toxicities.

Safety will be assessed by the collection of grade ≥3 adverse events, using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 - in all included patients.

To assess whether a change of the hormone therapy associated with palbociclib will benefit patients for whom rising ESR1 mutations are detected during treatment with palbociclib and aromatase inhibitor.

Progression-Free Survival (PFS) will be measured from the time of randomization to the time of tumor progression (as assessed by the investigator per RECIST v1.1) or death (whichever comes first) - in randomized patients.

To assess PFS in patients undergoing a cross-over following RECIST tumor progression in Arm A, from the start of crossover.

Progression-Free Survival will be measured from the time of cross-over to the time of tumor progression (as assessed by the investigator per RECIST 1.1) or death (whichever comes first) - in all patients with crossover

To report efficacy (PFS based on RECIST) of palbociclib combined with hormone therapy (aromatase inhibitor or fulvestrant), from the date of initial inclusion into the trial.

Progression-Free Survival will be measured from the time of inclusion to the time of tumor progression (as assessed by the investigator per RECIST 1.1) or death (whichever comes first) - in all included patients including those who switched to fulvestrant.

To assess whether the early switch (switch following ESR1 mutations increase) to fulvestrant contributes to a longer time to strategy failure than a late switch (cross-over following RECIST tumor progression).

Time to strategy failure will be measured from the time of randomization until palbociclib+endocrine therapy discontinuation or death (whichever comes first) - in all randomized patients.

To assess whether the early switch (following ESR1 mutations increase) to fulvestrant contributes a longer chemotherapy-free survival than a late switch (cross-over following RECIST tumor progression).

Chemotherapy-free survival will be measured from the time of randomization until the date of chemotherapy initiation or death (whichever comes first) - in all randomized patients.

To obtain additional safety data in a broad patient population treated with palbociclib and hormone therapy (aromatase inhibitor or fulvestrant) in a general Description of all extra-hematological grade ≥3 toxicities and SAEs incidence rate in the overall population and each treatment step

Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.

The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.

All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

To report the anti-cancer treatments received after the first line therapy.

The overall survival is the length of time from inclusion that patients enrolled in the study are still alive.

Spots Global Cancer Trial Database for esr1 mutation detection, ctdna