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

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.

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.