Palbociclib Plus Fulvestrant in Women With Hormone Receptor Positive and Human Epidermal Growth Factor Receptor Type 2 Negative Locally Advanced or Metastatic Breast Cancer Previously Treated With a CDK4/6 Inhibitor in Combination With Hormonal Therapy

The aim of the present study is to evaluate the efficacy and safety of palbociclib plus fulvestrant after failure of a combined treatment of hormonal therapy (aromatase inhibitor or tamoxifen ± LHRHa) plus a CDK4/6 inhibitor, in women with HR+ and HER2- LABC or MBC.

Primary endpoint:

1. To assess the clinical benefit rate (CBR) of the combination treatment palbociclib plus fulvestrant at progression of a combined treatment of hormonal therapy (aromatase inhibitor or tamoxifen ± LHRHa) and a CDK4/6 inhibitor.

   Clinical benefit rate for primary efficacy endpoints derivation will be based on the local (treating center's) radiologist's/investigator's tumor assessment.
   * For patients with measurable disease at baseline, progression will be determined according to the RECIST criteria v1.1.
   * In the absence of measurable disease at baseline, patients with bone only lesions, lytic or mixed (lytic + sclerotic), will be allowed to enter the study and the following will be considered disease progression among these patients:
   * The appearance of one or more new lytic lesions in bone,
   * The appearance of one or more new lesions outside of bone,
   * Unequivocal progression of existing bone lesions.

   Note: Pathologic fracture, new compression fracture, or complications of bone metastases will not be considered as evidence of disease progression, unless one of the above-mentioned criteria is fulfilled.
2. To assess the Quality of Life (QoL) of patients receiving the combination treatment palbociclib plus fulvestrant at progression of a combined treatment of hormonal therapy (aromatase inhibitor or tamoxifen ± LHRHa) and a CDK4/6 inhibitor.

Secondary Endpoints:

1. To evaluate the efficacy of the combination of fulvestrant plus palbociclib at the progression of a combined treatment of hormonal therapy (aromatase inhibitor or tamoxifen ± LHRHa) and CDK4/6 inhibitors with respect to:

   * Overall response rate (ORR)
   * Progression Free Survival (PFS)
   * Overall Survival (OS)
   * Safety and tolerability
2. To assess predictive biomarkers of response/resistance to fulvestrant plus palbociclib using metastatic tumor tissue samples and liquid biopsies.

This study will be performed in pre- and post-menopausal women with HR+/HER2- LABC or MBC whose disease is progressing to a CDK4/6 inhibitor in combination with hormonal therapy (aromatase inhibitor or tamoxifen ± LHRHa).

Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first.

This is a Phase II, multicentre, single-arm study following a Simon's two-stage optimal design

Screening phase At screening, the investigator or his/her authorized designee will assign a unique number to patients being considered for the study. The patient should provide a signed Informed Consent Form prior to any study screening evaluations. Once the patient Informed Consent Form has been signed and eligibility is confirmed (all inclusion/exclusion criteria has been verified), the patient can be enrolled. All screening evaluations will be performed within 28 days prior to Treatment Day 1. Patients may be re-screened.

Treatment phase Eligible patients will receive Fulvestrant plus palbociclib. Patients will be treated with fulvestrant 500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter and palbociclib125 mg oral day 1 to 21 every 28 days.

Dose adjustment (reduction, interruption) according to toxicity of study treatment will be allowed. Study treatment will continue until one of the following conditions apply - whichever comes first:

* tumor progression
* unacceptable toxicity according to investigator's judgment
* death
* discontinuation from the study for any other reason Further treatments after discontinuation will be at the investigator's discretion. During the study, visits will be performed monthly and at the end of treatment. Tumor assessment will be performed every 3 cycle of treatment.

For each patient enrolled in the present study a blood sample (mandatory) at study enrollment and at disease progression (mandatory) will be provided. Additionally, a tissue sample from the most accessible metastatic site will be collected at study enrollment and at disease progression (optional). Blood and tumor samples will be used to investigate the mechanisms of response and resistance to therapy with palbociclib in combination with fulvestrant.

Eligibility Criteria:
Inclusion Criteria:

1. Adult (≥ 18 years of age) pre or post-menopausal women with LABC or MBC not amenable to curative treatment by surgery or radiotherapy, progressing to a CDK4/6 inhibitor in combination with aromatase inhibitor or tamoxifen in the adjuvant or metastatic setting. To be enrolled in the present trial patients must have relapsed at least after 12 months from the last CDK4/6 dosage in the adjuvant setting or at progression from a first line combined hormonal treatment for metastatic disease with a CDK4/6 inhibitor plus AI or Tam with duration of, at least, 6 months. For metastatic disease, patients must have achieved, at least a stable disease while the first line hormonal treatment with a CDK4/6 inhibitor plus AI or Tam to be enrolled in the trial.
2. Patients receiving up to one line of chemotherapy before the first line hormonal treatment with a CDK4/6 inhibitor for metastatic disease may be enrolled in the study.
3. Histological confirmation of ER and/or PgR ≥ 1% and HER2 negative breast cancer (IHC status 0, 1+, 2+ and FISH not amplified).
4. Premenopausal women: in order to be eligible must have achieved surgical menopause with bilateral oophorectomy or ovarian radiation or medical menopause by treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (LHRHa) for induction of ovarian suppression.
5. Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrollment.
6. Patients who received ≤ 28 days of fulvestrant for second line advanced breast cancer treatment prior to study enrollment are eligible.
7. Patients must have:

   * At least one lesion that can be accurately measured in at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI
   * Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above.
8. Adequate bone marrow and coagulation and adequate organ function defined as follows:

   * ANC \> 1,000/mm3 (1.0 x 109/L);
   * Platelets \> 75,000/mm3 (75 x 109/L);
   * Hemoglobin≥ 9 g/dL (90 g/L);
   * Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 60 ml/min as calculated using the method standard for the institution;
   * Total serum bilirubin≤1.5 x ULN (\<2.5 ULN if Gilbert's disease);
   * AST and/or ALT≤ 3 x ULN (≤ 5 x ULN if liver metastases present);
   * Alkaline phosphatase ≤2.5 x ULN (≤ 5 x ULN if bone or liver metastases present);
   * ECOG Performance Status≤ 2;
   * Resolution of all acute toxic effects of prior therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade ≤1 (except alopecia).
9. Estimated life expectancy of \>12 weeks.
10. Patients must perform liquid biopsy at study entry and at disease progression. Tissue biopsy of the most accessible metastatic site at study entry and at disease progression are required but not mandatory.
11. Written informed consent obtained before any screening procedure and according to local guidelines.

Exclusion Criteria:

1. HER2-overexpressing patients by local laboratory testing (IHC3+ staining or in situ hybridization positive).
2. Patients who received \> 1 line of chemotherapy as treatment for MBC.
3. Patients who received \> 1 line of a CDK4/6 inhibitor in combination with hormonal treatment for LABC or MBC or who have relapsed at less than 12 months from the end of adjuvant treatment with a CDK4/6 inhibitor. For metastatic disease, patients with a progressive disease within the first 6 months of treatment while on first line therapy with a CDK4/6 inhibitor, will be excluded.
4. Patients receiving chemotherapy or any type of hormonal therapy after treatment with a CDK4/6 inhibitor for metastatic disease.
5. Patients interrupting the previous treatment with CDK4/6 inhibitor for cardiac and/or hepatic toxicity and not for disease progression.
6. Pregnant, lactating women.
7. Known hypersensitivity to CDK4/6 inhibitors, fulvestrant, or to any of the excipients.
8. Radiotherapy within four weeks prior to enrollment (baseline/treatment start) except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment (baseline/treatment start). Patients must have recovered from radiotherapy toxicities prior to enrollment.
9. Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.
10. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below:

    1. short duration (\<2 weeks) of systemic corticosteroids is allowed (e.g., chronic obstructive pulmonary disease, anti-emetic);
    2. low doses of corticosteroids for brain metastasis treatment is allowed.
11. Patients with symptomatic visceral disease in need of urgent disease control (e.g., significant dyspnea related to pulmonary lymphangitic carcinomatosis and lung metastases or clinically meaningful symptomatic liver metastasis at the judgement of treating investigator).
12. Symptomatic brain metastases.
13. Patients with a known history of HIV seropositivity.
14. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin, low-molecular-weight heparin (LMWH) and acetylsalicylic acid or equivalent, as long as the INR is ≤ 2.0).
15. Any severe and/or uncontrolled medical conditions such as: unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia.
16. Acute and chronic, active infectious disorders.
17. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study treatments (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).
18. Inability to swallow oral medications.
19. Significant symptomatic deterioration of lung function.
20. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to enrollment.
21. History of non-compliance to medical regimens.
22. Patients refusing to perform liquid biopsy at study entry and disease progression.
23. Patients unwilling to or unable to comply with the protocol.