PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection
NCT ID: NCT03079011
Last Updated: 2025-11-18
Study Results
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Basic Information
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COMPLETED
PHASE3
1017 participants
INTERVENTIONAL
2017-03-22
2025-09-22
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
SEQUENTIAL
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.
TREATMENT
NONE
Study Groups
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A- palbociclib + AI
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.
Palbociclib 125mg
Palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle
Aromatase Inhibitors
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)
B- Palbociclib + fulvestrant
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.
Palbociclib 125mg
Palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle
Fulvestrant Injectable Product
500 mg by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days)
Selection - Palbociclib + AI
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 125mg
Palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle
Aromatase Inhibitors
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)
Interventions
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Palbociclib 125mg
Palbociclib 125 mg once daily for 21 days followed by 7 days off to complete a 28-day cycle
Aromatase Inhibitors
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)
Fulvestrant Injectable Product
500 mg by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days)
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Age ≥18 years;
3. Life expectancy \>3 months;
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
5. Estrogen Receptor (ER)-positive and HER2-negative breast cancer. Where available, assessment of Estrogen Receptor status should be based on the most recent tumor sample; to be considered as ER-positive, the most recent breast cancer tissue examined must display at least 10% of cancer cells with positive ER staining;
6. Tumor block (primary tumor or metastasis) available;
7. No prior systemic anti-cancer therapy for metastatic or advanced disease (chemotherapy, targeted therapy or hormone therapy); prior initiation of LHRH agonist or bone-directed agents is however allowed);
8. Menopausal patients or patients with suppressed ovarian function
* Women with bilateral oophorectomy
* Postmenopausal women, as defined by any of the following criteria:
* Age 60 or over;
* Age 50 to 59 years and meets one of the following criteria:
* Amenorrhea for ≥24 months and follicle-stimulating hormone within the postmenopausal range;
* patients with hysterectomy or chemotherapy-induced amenorrhea must display follicle-stimulating hormone within the postmenopausal range;
* Other women, provided they are being treated with monthly LHRH analogues (first injection performed ≥7 days before the treatment initiation) and are willing to continue to receive LHRH agonist therapy for the duration of the trial;
9. Patients may have measurable (according to Response Evaluation Criterion in Solid Tumors (RECIST v1.1) or not measurable disease
* Patients with only blastic bone lesions are not eligible;
* Patients with only pleural, cardiac or peritoneal effusion or meningeal carcinomatosis are not eligible;
10. Adequate organ and marrow function as defined below:
* Hemoglobin ≥90 g/L
* Absolute neutrophil count ≥1.5 g/L
* Platelet count ≥100 g/L
* Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome.
* ALT and AST ≤3 × ULN;
* Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present)
* Serum creatinine ≤1.5 × ULN or calculated creatinine clearance ≥ 60 mL/min as determined by Cockcroft-Gault (using actual body weight) formula for females \[creatinine clearance =Weight (kg) × (140 - Age) × 0.85 (mL/min)/ (72 × serum creatinine (mg/dL))
11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and any protocol-related procedures including screening evaluations;
12. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.03 Grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion);
13. Written informed consent obtained prior to performing any protocol-related procedures including screening evaluations;
14. Patient affiliated to a social security system.
Exclusion Criteria
2. Her2-positive or equivocal tumor status either on the primary or on the recurrent tumor, defined as IHC3+, Fish/Cish amplified or Fish/Cish equivocal according to the ASCO2015 criteria;
3. Prior endocrine therapy in the metastatic setting is not allowed;
4. Prior treatment with any CDK 4/6 inhibitor in the adjuvant or metastatic setting (neoadjuvant/preoperative treatment is allowed); however, prior therapy with another targeted treatment in the adjuvant setting is allowed;
5. Visceral crisis: Advanced, symptomatic, visceral spread that is at risk of life-threatening complication in the short term and that requires chemotherapy;
6. Any major surgery (defined as requiring general anaesthesia) or significant traumatic injury within 4 weeks of treatment initiation or patients that may require major surgery during the course of the study; however, surgical diagnostic procedure is allowed (even if performed under general anaesthesia);
7. Known, active bleeding diathesis;
8. Any serious known concomitant systemic disorder (e.g. known active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator), previous history of bleeding diathesis, or anti-coagulation treatment (the use of low molecular weight heparin is allowed);
9. Patients unable to swallow tablets;
10. History of mal-absorption syndrome or other condition that would interfere with enteral absorption;
11. Chronic daily treatment with corticosteroids with a dose of ≥10 mg/day methylprednisolone equivalent (excluding inhaled steroids);
12. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable and off anticonvulsants and steroids for at least 4 weeks before treatment start;
13. Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, palbociclib or any of their excipients;
14. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia);
15. Patients treated within the last 7 days prior to treatment start in the trial with drug that are known to be CYP3A4 inhibitors, drugs that are known to be CIP3A4 inducers, who underwent a grapefruit cure;
16. Patients already included in another therapeutic trial evaluating an investigational medicinal product or having received an investigational medicinal product within 3 months;
17. History of previous:
* Any other stage II, III, IV cancer within 5 years preceding patient enrollment in the trial - however, multiple primary breast cancers (controlateral/ipsilateral cancers/local relapses) are allowed pending all tumor masses were ER+;
* Any history of hematological malignancy;
18. Persons deprived of their freedom or under guardianship or incapable of giving consent;
19. Pregnancy or lactation period. Women of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization; LHRH agonist cannot be considered as an efficient contraceptive measure) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months.
18 Years
FEMALE
No
Sponsors
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Pfizer
INDUSTRY
UNICANCER
OTHER
Responsible Party
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Principal Investigators
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François-Clément BIDARD, MD PhD
Role: PRINCIPAL_INVESTIGATOR
Institut Curie
Suzette DELALOGE, MD PhD
Role: PRINCIPAL_INVESTIGATOR
Gustave Roussy, Cancer Campus, Grand Paris
Anne-Claire HARDY BESSARD, MD
Role: PRINCIPAL_INVESTIGATOR
Centre Armoricain d'Oncologie
Locations
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Centre Antoine Lacassagne
Nice, , France
CHP Saint Grégoire
Saint-Grégoire, , France
Centre ONCOGARD - Institut de Cancérologie du Gard
Nîmes, , France
Institut Curie
Paris, , France
Hopital Diaconesses-Croix Saint Simon
Paris, , France
Hopital Européen Georges Pompidou
Paris, , France
Saint Louis Hospital
Paris, , France
Centre Hospitalier de Pau
Pau, , France
Centre Catalan d'Oncologie
Perpignan, , France
Polyclinique Francheville
Périgueux, , France
Centre Hospitalier Lyon Sud
Pierre-Bénite, , France
CARIO - Centre Armoricain Radiothérapie Imagerie Médicale et Oncologi
Plérin, , France
Centre Hospitalier de Cornouaille
Quimper, , France
Clinique de la Croix du Sud
Quint-Fonsegrives, , France
Centre Eugène Marquis
Rennes, , France
Centre de radiothérapie et d'oncologie médicale LE-CROME
Ris-Orangis, , France
Centre Henri Becquerel
Rouen, , France
Centre Hospitalier Saint-Brieuc
Saint-Brieuc, , France
Institut Curie - Hôpital René Huguenin
Saint-Cloud, , France
Centre Hospitalier Universitaire
Amiens, , France
Clinique de l'Europe
Amiens, , France
Institut de Cancérologie de l'Ouest - Site Paul Papin
Angers, , France
Centre Hospitalier d'Auxerre
Auxerre, , France
Institut Sainte Catherine
Avignon, , France
Centre Hospitalier de Beauvais
Beauvais, , France
Centre Hospitalier de Blois
Blois, , France
Clinique Tivoli Ducos
Bordeaux, , France
Institut Bergonié
Bordeaux, , France
Polyclinique Bordeaux Nord Aquitaine
Bordeaux, , France
Centre Hospitalier de boulogne sur Mer
Boulogne-sur-Mer, , France
Centre Hospitalier Fleyriat
Bourg-en-Bresse, , France
CHRU Morvan
Brest, , France
Clinique PASTEUR-CFRO
Brest, , France
Centre Francois Baclesse
Caen, , France
Centre Hospitalier René Dubos
Cergy-Pontoise, , France
Medipole de Savoie
Challes-les-Eaux, , France
Centre Hôpital Sainte Marie
Chalon-sur-Saône, , France
CH William Morey
Chalon-sur-Saône, , France
Centre Hospitalier Métropole de Savoie
Chambéry, , France
Centre Hospitalier de Cholet
Cholet, , France
Centre Jean Perrin
Clermont-Ferrand, , France
Pôle Santé République
Clermont-Ferrand, , France
Centre Georges François Leclerc
Dijon, , France
CHI Fréjus St-Raphaël
Fréjus, , France
Institut Daniel Hollard - Groupe Hospitalier Mutualiste de Grenoble
Grenoble, , France
Centre Hospitalier Départemental de Vendée
La Roche-sur-Yon, , France
Clinique du Cap d'Or
La Seyne-sur-Mer, , France
Centre Hospitalier de Versailles
Le Chesnay, , France
Centre Hospitalier le Mans
Le Mans, , France
Institut Hospitalier Franco-Britannique
Levallois-Perret, , France
CHU Dupuytren
Limoges, , France
Clinique François Chénieux
Limoges, , France
Centre Hospitalier Bretagne Sud
Lorient, , France
Centre Leon Berard
Lyon, , France
Clinique de la Sauvegarde
Lyon, , France
Hôpital privé Jean Mermoz
Lyon, , France
Hôpital Européen Marseille
Marseille, , France
Hôpital Saint Joseph
Marseille, , France
Institut Paoli Calmettes
Marseille, , France
Centre d'Oncologie radiothérapie de Macon
Mâcon, , France
Clinique Claude Bernard
Metz, , France
Centre Hospitalier ANNECY GENEVOIS
Metz-Tessy, , France
CH Mont de Marsan
Mont-de-Marsan, , France
Centre Hospitalier Montceau les mines
Montceau-les-Mines, , France
ICM - Val d'Aurelle
Montpellier, , France
Centre d'Oncologie de Gentilly
Nancy, , France
Hopital Privé du Confluent
Nantes, , France
Institut de Cancérologie de l'Ouest - Site René Gauducheau
Saint-Herblain, , France
Clinique Mutualiste de l'Estuaire
Saint-Nazaire, , France
Institut de cancérologie lucien Neuwith
Saint-Priest-en-Jarez, , France
Centre Hospitalier de Broussais
St-Malo, , France
Centre Paul Stauss
Strasbourg, , France
Clinique de l'Orangerie
Strasbourg, , France
Clinique Sainte Anne
Strasbourg, , France
Hôpitaux Universitaires de Strasbourg
Strasbourg, , France
Hôpitaux du Léman
Thonon-les-Bains, , France
Clinique Pasteur
Toulouse, , France
Institut Claudius Regaud
Toulouse, , France
Centre Hospitalier de Tours - Hopital Bretonneau
Tours, , France
Centre Hospitalier Bretagne Atlantique
Vannes, , France
UNEOS Site Hôpital Robert Schuman
Vantoux, , France
Gustave Roussy
Villejuif, , France
Countries
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References
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Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, Andre F, Arnould L, Pradines A, Bieche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. doi: 10.1016/S1470-2045(22)00555-1. Epub 2022 Sep 29.
Berger F, Marce M, Delaloge S, Hardy-Bessard AC, Bachelot T, Bieche I, Pradines A, De La Motte Rouge T, Canon JL, Andre F, Arnould L, Clatot F, Lemonnier J, Marques S, Bidard FC; PADA-1 investigators. Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1. BMJ Open. 2022 Mar 3;12(3):e055821. doi: 10.1136/bmjopen-2021-055821.
Other Identifiers
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2016-004360-18
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
UC-0140/1615 - UCBG3-05
Identifier Type: -
Identifier Source: org_study_id
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