PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection

Metastatic Breast Cancer Clinical Trial

— PADA-1  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03079011
• Other study ID #: UC-0140/1615 - UCBG3-05
• Secondary ID: 2016-004360-18
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 22, 2017
• Est. completion date: June 30, 2025

Study information

• Verified date: September 2023
• Source: UNICANCER
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1017
• Est. completion date: June 30, 2025
• Est. primary completion date: April 30, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Women with proven loco-regionally recurrent or metastatic adenocarcinoma of the breast not amenable to curative therapy with disease considered potentially sensitive to aromatase inhibitors Note: patients relapsing while on adjuvant tamoxifen or other non-aromatase inhibitor adjuvant endocrine therapy and patients relapsing more than one year after the end of aromatase inhibitor adjuvant therapy are eligible for the present study;

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:

1. Locally advanced breast cancer or loco-regional relapse amenable for any treatment with curative intent;

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• 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)

Locations

Country	Name	City	State
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-saone
France	CH William Morey	Chalon-sur-saone
France	Centre Hospitalier Métropole de Savoie	Chambery
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	Frejus
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	Centre d'Oncologie radiothérapie de Macon	Macon
France	Hôpital Européen Marseille	Marseille
France	Hôpital Saint Joseph	Marseille
France	Institut Paoli Calmettes	Marseille
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	Centre Antoine Lacassagne	Nice
France	Centre ONCOGARD - Institut de Cancérologie du Gard	Nimes
France	Hopital Diaconesses-Croix Saint Simon	Paris
France	Hopital Européen Georges Pompidou	Paris
France	Institut Curie	Paris
France	Saint Louis Hospital	Paris
France	Centre Hospitalier de Pau	PAU
France	Polyclinique Francheville	Perigueux
France	Centre Catalan d'Oncologie	Perpignan
France	Centre Hospitalier Lyon Sud	Pierre-benite
France	CARIO - Centre Armoricain Radiothérapie Imagerie Médicale et Oncologi	Plerin
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	CHP Saint Grégoire	Saint Gregoire
France	Institut de cancérologie lucien Neuwith	Saint Priest En Jarez
France	Centre Hospitalier Saint-Brieuc	Saint-Brieuc
France	Institut Curie - Hôpital René Huguenin	Saint-cloud
France	Institut de Cancérologie de l'Ouest - Site René Gauducheau	Saint-herblain
France	Centre Hospitalier de Broussais	Saint-malo
France	Clinique Mutualiste de l'Estuaire	Saint-nazaire
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

Sponsors (2)

Lead Sponsor	Collaborator
UNICANCER	Pfizer

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of treatment-emergent Adverse Events	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.	Throughout study completion, up to 4 years
Primary	Progression-free survival (Step 2)	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.	From randomization to disease progression or death, up to 4 years
Secondary	Progression-free survival (step 3)	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	From cross-over, up to 4 years
Secondary	Progression-free survival (step 1&2)	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.	From inclusion, up to 4 years
Secondary	Time to strategy failure from randomization (Step 2 and 3)	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.	From randomization, up to 4 years
Secondary	Chemotherapy-free survival (Step 2 and 3)	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.	From randomization, up to 4 years
Secondary	Incidence of treatment-emergent extra-hematological Adverse Events	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	Throughout study completion, up to 4 years
Secondary	Quality of life by quality of life questionnaire (QLQ)-C30	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.	From inclusion and every 2 months until disease progression, up to 2 years
Secondary	Other line of therapy	To report the anti-cancer treatments received after the first line therapy.	Throughout study completion, up to 4 years
Secondary	Overall Survival	The overall survival is the length of time from inclusion that patients enrolled in the study are still alive.	Throughout study completion, up to 4 years