Clinical trial NCT03079011: PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Keywords: ESR1 mutation detection, ctDNA
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2017-03-14
Enrollment: 1017
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of treatment-emergent Adverse Events
timeFrame: Throughout study completion, up to 4 years
measure: Progression-free survival (Step 2)
timeFrame: From randomization to disease progression or death, up to 4 years
Secondary outcomes:
measure: Progression-free survival (step 3)
timeFrame: From cross-over, up to 4 years
measure: Progression-free survival (step 1&2)
timeFrame: From inclusion, up to 4 years
measure: Time to strategy failure from randomization (Step 2 and 3)
timeFrame: From randomization, up to 4 years
measure: Chemotherapy-free survival (Step 2 and 3)
timeFrame: From randomization, up to 4 years
measure: Incidence of treatment-emergent extra-hematological Adverse Events
timeFrame: Throughout study completion, up to 4 years
measure: Quality of life by quality of life questionnaire (QLQ)-C30
timeFrame: From inclusion and every 2 months until disease progression, up to 2 years
measure: Other line of therapy
timeFrame: Throughout study completion, up to 4 years
measure: Overall Survival
timeFrame: Throughout study completion, up to 4 years
Other outcomes:
Locations:
city: Amiens
country: France
facility: Centre Hospitalier Universitaire
city: Amiens
country: France
facility: Clinique de l'Europe
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest - Site Paul Papin
city: Auxerre
country: France
facility: Centre Hospitalier d'Auxerre
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Beauvais
country: France
facility: Centre Hospitalier de Beauvais
city: Blois
country: France
facility: Centre Hospitalier de Blois
city: Bordeaux
country: France
facility: Clinique Tivoli Ducos
city: Bordeaux
country: France
facility: Institut Bergonié
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord Aquitaine
city: Boulogne Sur Mer
country: France
facility: Centre Hospitalier de boulogne sur Mer
city: Bourg En Bresse
country: France
facility: Centre Hospitalier Fleyriat
city: Brest
country: France
facility: CHRU Morvan
city: Brest
country: France
facility: Clinique PASTEUR-CFRO
city: Caen
country: France
facility: Centre Francois Baclesse
city: Cergy - Pontoise
country: France
facility: Centre Hospitalier René Dubos
city: Challes Les Eaux
country: France
facility: Medipole de Savoie
city: Chalon-sur-saone
country: France
facility: Centre Hôpital Sainte Marie
city: Chalon-sur-saone
country: France
facility: CH William Morey
city: Chambery
country: France
facility: Centre Hospitalier Métropole de Savoie
city: Cholet
country: France
facility: Centre Hospitalier de Cholet
city: Clermont-ferrand
country: France
facility: Centre Jean Perrin
city: Clermont-ferrand
country: France
facility: Pôle Santé République
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Frejus
country: France
facility: CHI Fréjus St-Raphaël
city: Grenoble
country: France
facility: Institut Daniel Hollard - Groupe Hospitalier Mutualiste de Grenoble
city: La Roche Sur Yon
country: France
facility: Centre Hospitalier Départemental de Vendée
city: La Seyne-sur-Mer
country: France
facility: Clinique du Cap d'Or
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles
city: Le Mans
country: France
facility: Centre Hospitalier le Mans
city: Levallois-perret
country: France
facility: Institut Hospitalier Franco-Britannique
city: Limoges
country: France
facility: CHU Dupuytren
city: Limoges
country: France
facility: Clinique François Chénieux
city: Lorient
country: France
facility: Centre Hospitalier Bretagne Sud
city: Lyon
country: France
facility: Centre Leon Berard
city: Lyon
country: France
facility: Clinique de la Sauvegarde
city: Lyon
country: France
facility: Hôpital privé Jean Mermoz
city: Macon
country: France
facility: Centre d'Oncologie radiothérapie de Macon
city: Marseille
country: France
facility: Hôpital Européen Marseille
city: Marseille
country: France
facility: Hôpital Saint Joseph
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Metz-Tessy
country: France
facility: Centre Hospitalier ANNECY GENEVOIS
city: Metz
country: France
facility: Clinique Claude Bernard
city: Mont de Marsan
country: France
facility: CH Mont de Marsan
city: Montceau-les-mines
country: France
facility: Centre Hospitalier Montceau les mines
city: Montpellier
country: France
facility: ICM - Val d'Aurelle
city: Nancy
country: France
facility: Centre d'Oncologie de Gentilly
city: Nantes
country: France
facility: Hopital Privé du Confluent
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nimes
country: France
facility: Centre ONCOGARD - Institut de Cancérologie du Gard
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hopital Diaconesses-Croix Saint Simon
city: Paris
country: France
facility: Hopital Européen Georges Pompidou
city: Paris
country: France
facility: Saint Louis Hospital
city: PAU
country: France
facility: Centre Hospitalier de Pau
city: Perigueux
country: France
facility: Polyclinique Francheville
city: Perpignan
country: France
facility: Centre Catalan d'Oncologie
city: Pierre-benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Plerin
country: France
facility: CARIO - Centre Armoricain Radiothérapie Imagerie Médicale et Oncologi
city: Quimper
country: France
facility: Centre Hospitalier de Cornouaille
city: Quint Fonsegrives
country: France
facility: Clinique de la Croix du Sud
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Ris Orangis
country: France
facility: Centre de radiothérapie et d'oncologie médicale LE-CROME
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Gregoire
country: France
facility: CHP Saint Grégoire
city: Saint Priest En Jarez
country: France
facility: Institut de cancérologie lucien Neuwith
city: Saint-Brieuc
country: France
facility: Centre Hospitalier Saint-Brieuc
city: Saint-cloud
country: France
facility: Institut Curie - Hôpital René Huguenin
city: Saint-herblain
country: France
facility: Institut de Cancérologie de l'Ouest - Site René Gauducheau
city: Saint-malo
country: France
facility: Centre Hospitalier de Broussais
city: Saint-nazaire
country: France
facility: Clinique Mutualiste de l'Estuaire
city: Strasbourg
country: France
facility: Centre Paul Stauss
city: Strasbourg
country: France
facility: Clinique de l'Orangerie
city: Strasbourg
country: France
facility: Clinique Sainte Anne
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg
city: Thonon-les-Bains
country: France
facility: Hôpitaux du Léman
city: Toulouse
country: France
facility: Clinique Pasteur
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Tours
country: France
facility: Centre Hospitalier de Tours - Hopital Bretonneau
city: Vannes
country: France
facility: Centre Hospitalier Bretagne Atlantique
city: Vantoux
country: France
facility: UNEOS Site Hôpital Robert Schuman
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: Institut Curie
name: François-Clément BIDARD, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Suzette DELALOGE, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Armoricain d'Oncologie
name: Anne-Claire HARDY BESSARD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.