Neoplasms

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Breast Neoplasms

Breast Diseases

Skin Diseases

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Antineoplastic Agents

Hormones

Fulvestrant

Mitogens

Palbociclib

Protein Kinase Inhibitors

Enzyme Inhibitors

Single-arm study with the primary objective of assessing the efficacy and safety of palbociclib in combination with fulvestrant (Faslodex) in women with HR+, HER2-negative metastatic breast cancer, regardless of their menopausal status, whose disease has progressed after prior treatment with AI plus a CDK4/6 inhibitor.

Patients will be enrolled into the study and assign to receive Palbociclib 125 mg/day orally for 3 weeks followed by 1 week off plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, every 28 days (+/- 7 days) thereafter starting from Day 1 of Cycle 1

Grazia Arpino, MD

Giuseppina Sanna, MD

Salvatore Del Prete, MD

Fabio Puglisi, MD

Filippo Montemurro, MD

Antonio Febbraro, MD

Paola Lucia Poletti, MD

Saverio Cinieri, MD

Lucia Del Mastro, MD

Giuseppe Cairo, MD

Vincenzo Adamo, MD

Angela Toss, MD

Michele Orditura, MD

Ferdinando Riccardi, MD

Vincenzo Montesarchio, MD

Michelino De Laurentiis, MD

Andrea Michelotti, MD

Alessandra Fabi, MD

Teresa Gamucci, MD

Carmine De Angelis, MD

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.

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

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

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: a Multicenter, Phase II Trial

To assess the clinical benefit rate (CBR) of the treatment, the Clinical Benefit Response (CBR) is defined as complete response (CR) or partial response (PR) or stable disease (SD) \>24 weeks according to the RECIST version 1.1 recorded in the time period between enrollment and disease progression or death of any cause. CBR with the corresponding 95% Confidence Interval (95% C.I.) will be estimated using the exact binomial method. A Simon optimal two-stage design will be used to exclude a clinical benefit rate (CBR) of 30% (p0 = 0.30) with a clinical relevant target of 40% (p1 = 0.40) using a one-sided alpha-level of 0.05 and a power of 0.80. Fifty-nine (59) subjects will be enrolled in the first phase. If nineteen (19) of fewer CR+PR+SD will be observed, the study will be terminated. Otherwise the treatment will be considered worthy of further investigation and 109 more subjects will be enrolled for a total sample size of 168 subjects.

Breast cancer-specific quality of life total scale scores and single item scale scores will be summarized by descriptive summary tables at baseline and over time. The mean changes from baseline will also be summarized using descriptive statistics. Longitudinal trajectories of total scale scores will be modelled using linear mixed models with random intercept to account for subject specific baseline assessment; time will be modeled continuously using days since baseline; potential non linear trend will be examined by adding quadratic terms to the model. Selection of the best model will be based on Akaike Information Criterion (AIC).

To evaluate the efficacy of the combination of fulvestrant plus palbociclib at the progression of a combined treatment of hormonal therapy and CDK4/6 inhibitors with respect to:

• Overall response rate (ORR) :will be estimated by dividing the number of patients with OR (CR or PR) by the number of patients ("response rate"). A 95% CI for the response rates will be provided using the exact binomial method

To evaluate the efficacy of the combination of fulvestrant plus palbociclib at the progression of a combined treatment of hormonal therapy and CDK4/6 inhibitors with respect to:

• Overall Survival (OS) :the median event times and 95% CIs will be estimated. The 1-year survival probability will be estimated using the Kaplan-Meier method and a two sided 95% CI for the log \[-log(1-year survival probability)\] will be calculated using a normal approximation using the Greenwood's formula

To evaluate the efficacy of the combination of fulvestrant plus palbociclib at the progression of a combined treatment of hormonal therapy and CDK4/6 inhibitors with respect to:

• Progression Free Survival (PFS) :the analyses of PFS will be performed in the ITT population. PFS time will be summarized using the Kaplan-Meier method and displayed graphically where appropriate. 95% CIs for the 25th, 50th and 75th percentiles of the event-free time (if reached) will be reported.

To assess predictive biomarkers of response/resistance to fulvestrant plus palbociclib using metastatic tumor tissue samples and liquid biopsies. Patients must perform liquid biopsy at study entry and at disease progression.

Biopsies will be used to investigate expression levels and/or genetic alteration of cell cycle components as well as additional molecular pathways potentially responsible for resistance to CDK4/6 inhibitors.

Spots Global Cancer Trial Database for human epidermal growth factor receptor type 2 negative