To Reverse ENDocrine Resistance Trial - PD 0332991 Monotherapy vs PD 0332991 in Combination With the Endocrine Therapy

Study Overview
=================
Brief Summary
-----------------
This study aims to assess the activity of PD0332991 in monotherapy and in combination with the endocrine therapy (anastrozole, letrozole, exemestane or fulvestrant) on which the patient has progressed in the previous line for advanced breast cancer in order to reverse endocrine resistance.

Detailed Description
-----------------
In a clinical context, there is a lack of molecular compounds with demonstrated clinical activity in delaying/reversing resistance to endocrine agents. CDK 4/6 inhibitors may represent a biologically-driven option in this context. With the present study investigators aim to complement the ongoing trial on PD0332991 by acquiring information on its clinical activity in post-menopausal patients with ER positive, Her2 negative advanced breast cancer patients already pretreated with a first-line or second line endocrine therapy.

Official Title
-----------------
Phase 2,Open-label,Multicenter,Randomized Study of PD0332991 (Oral CDK4/6 Inhibitor) Monotherapy and in Combination With the HT to Which the pt Has Progressed in the Previous Line for ER+,Her2- Post-menopausal Advanced Breast Cancer Pts

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Palbociclib
* Drug: Anastrozole
* Drug: Letrozole
* Drug: Exemestane
* Drug: Fulvestrant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven diagnosis of adenocarcinoma of the breast with evidence of metastatic disease ER positive tumor ≥ 10% HER2 negative breast cancer by FISH or IHC Progression of advanced breast cancer on first or second line endocrine therapy for advanced breast cancer Paraffin-embedded tumor available for centralized assessment of biomarkers Measurable disease according to RECIST 1.1 (bone only disease is allowed only if measurable). Postmenopausal status Eastern Cooperative Oncology Group (ECOG) Performance status 0 -2 Resolution of all acute toxic effects of prior therapy or surgical procedures to CTCAE grade >1 Adequate organ function Exclusion Criteria: Unstable brain metastases Prior treatment with more than one line of CT or more than two lines of HT advanced breast cancer or any CDK inhibitor Current treatment with therapeutic doses of anticoagulant Current use or anticipated need for food or drugs that are known strong CYP3A4 inhibitors / inducers, drugs that are predominantly metabolized by CYP3A with narrow therapeutic indices, drugs with the potential of prolonging QT interval Diagnosis of any secondary malignancy within the last 3 years Active inflammatory bowel disease or chronic diarrhea Known human immunodeficiency virus infection; active hepatitis C, active hepatitis B

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Palbociclib monoterapy | Drug: Palbociclib<br>* Palbociclib 125 mg/day orally in an ongoing 3:1 schedule (3 weeks on/1 week off)<br>* Other names: PD0332991;|
| Experimental: Arm B<br>Palbociclib + HT (Anastrozole, Letrozole, Exemestane, Fulvestrant) | Drug: Palbociclib<br>* Palbociclib 125 mg/day orally in an ongoing 3:1 schedule (3 weeks on/1 week off)<br>* Other names: PD0332991;Drug: Anastrozole<br>* Continuation of prior anastrozole 1mg/day orally in a continuous regimen<br>Drug: Letrozole<br>* Continuation of prior letrozole 2.5mg/day orally in a continuous regimen<br>Drug: Exemestane<br>* Continuation of prior exemestane 25mg/day orally in a continuous regimen<br>Drug: Fulvestrant<br>* Continuation of prior fulvestrant 500mg intramuscular injection every 4 weeks in a continuous regimen<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of complete response (CR), partial response (PR) or stable disease (SD) ≥24 weeks (clinical benefit) | All randomized patients with adequate baseline disease assessment with measurable disease, the disease under study and who start treatment on the assigned arm will be considered evaluable for clinical benefit (CB). The probability of CB on each randomized treatment arm will be estimated by dividing the number of patients with CB by the number of evaluable patients randomized to the treatment arm. | Baseline up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | PFS is the time from randomization date to date of first documentation of progression or death due to any cause, whichever occurs first. Documentation of progression must be by objective disease assessment as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. All patients randomized will be considered evaluable for PFS. | Baseline up to 3 years | 
| Objective Response (OR) | All randomized patients with adequate baseline disease assessment with measurable disease, the disease under study and who start treatment on the assigned arm will be considered evaluable for objective response (CR or PR). The probability of OR on each randomized treatment arm will be estimated by dividing the number of patients with OR by the number of evaluable patients randomized to the respective treatment arm (response rate). | Baseline up to 3 years | 
| Overall Survival (OS) | OS is the time from randomization date to date of death due to any cause. All patients randomized will be considered evaluable for OS. | Baseline up to 6 years | 
| Time to Progression (TTP) | TTP is the time from randomization date to date of first documentation of objective progression. All patients randomized will be considered evaluable for TTP. | Baseline up to 3 years | 
| Duration of Response (DR) | For patients with an objective response (CR or PR), duration of response is the time from first documentation of CR or PR to date of first documentation of objective progression or death. Date of first documentation of progression and date of first documentation of CR or PR will be based on investigator assessment of response. | Baseline up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Advanced breast cancer, Postmenopausal, ER positive, Her2 negative