Two Different Schedules of Palbociclib + Second Line Endocrine Therapy in Estrogen Receptor Positive, HER2 Neg Advanced/Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine if the combination of endocrine therapy and Palbociclib at a daily dose of 100 mg will result in a better response to therapy with fewer dose interruptions than the proposed dosing regimen of 125 mg daily for 21 days out of a 28 day cycle in combination with endocrine therapy.

Detailed Description
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The standard or usual treatment of this type of breast cancer is endocrine therapy. Palbociclib is a new type of drug for breast cancer. Laboratory tests as well as studies in animals and people show that it may help slow the growth of breast cancer. The most widely tested regimen of Palbociclib for patients with metastatic/advanced breast cancer is 125 mg every day for 21 days out of a 28 day cycle in combination with standard endocrine (hormone) therapy. This study explores if administering a lower dose of palbociclib - 100 mg given every day of a 28 day cycle in combination with standard endocrine (hormone) therapy - may result in more tumour shrinkage and be better tolerated.

Official Title
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Randomized Phase II Study Comparing Two Different Schedules of Palbociclib Plus Second Line Endocrine Therapy in Women With Estrogen Receptor Positive, HER2 Negative Advanced/Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Palbociclib 100mg
* Drug: Palbociclib 125mg
* Drug: Fulvestrant or Tamoxifen or Aromatase Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal and postmenopausal women 18 years of age or older. Histologically confirmed adenocarcinoma of the breast, with ER positive and HER2 negative status based on local testing on most recent pathological tumour specimen. Patients must satisfy the following criteria for prior therapy: Progressed during treatment or within 12 months of completion of adjuvant endocrine therapy or Progressed during prior endocrine therapy for advanced/metastatic disease. Note: 'Progressed during endocrine therapy' means that the patient progressed while on or within 1 month after discontinuation of endocrine therapy. One line of chemotherapy for advanced/metastatic disease (regardless of prior adjuvant chemotherapy use) is allowed in addition to endocrine therapy. Patients must have evidence of disease to be eligible for the study, but measurable disease is not mandatory. For those patient with measureable disease who will be included in the response assessment, the following criteria must apply: X-ray ≥ 20 mm Spiral CT scan or physical exam ≥ 10 mm (lymph nodes must be ≥ 15 mm in the short axis) Conventional CT scan, MRI ≥ 20 mm Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented. Tumor lesions previously irradiated or subjected to other loco regional therapy will only be deemed measurable if progression at the treated site after completion of therapy is clearly documented. Eastern Cooperative Oncology Group (ECOG) 0-2. Adequate organ and bone marrow function as defined by: ANC ≥ 1,500/mm3 (1.5 x 109/L) Platelets ≥ 100,000/mm3 (100 x 109/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 (<3 ULN if Gilbert's disease). Patient must agree to provide tumour tissue from the most recent pathological tumour specimen. Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits placed on patients being considered for this trial. In accordance with NCIC CTG policy, protocol treatment is to begin within 2 working days of patient randomization. Women of childbearing potential must have agreed to use a highly effective contraceptive method. Exclusion Criteria: Patients with advanced, symptomatic, visceral spread that are at risk of life threatening complication in the short term. Patients with symptomatic CNS involvement, meningeal or parenchymal, that is uncontrolled or requires steroids. Prior treatment with any CDK 4/6 inhibitor. Prior treatment with mTOR inhibitors. Active second malignancy, regardless of ongoing treatment. Any concurrent medical condition that in the opinion of the investigator would interfere with the safe administration of the study drug and participation in the study. Participation in a prior anti-cancer investigational study within 30 days prior to enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Palbociclib (100mg)<br>Palbociclib 100mg PO daily plus Fulvestrant or Tamoxifen or another Aromatase Inhibitor at the standard doses/schedules | Drug: Palbociclib 100mg<br>* 100mg PO daily<br>Drug: Fulvestrant or Tamoxifen or Aromatase Inhibitor<br>* given at the standard doses/schedules<br>|
| Active Comparator: Palbociclib (125mg)<br>Palbociclib 125mg PO daily 3 out of 4 weeks plus Fulvestrant or Tamoxifen or another Aromatase Inhibitor at the standard doses/schedules | Drug: Palbociclib 125mg<br>* 125mg PO daily 3 weeks out of 4<br>Drug: Fulvestrant or Tamoxifen or Aromatase Inhibitor<br>* given at the standard doses/schedules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival Using the RECIST 1.1 Criteria | progression free survival (PFS) is defined as time from randomization to progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Response or No Response | Response rate = Number of (Complete response + partial response) / total treated patients. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 2 years | 
| Duration of Response | For patients with complete or partial response, duration of response is defined as days from first recorded response to the first date of recurrent or progression or death. | 2 years | 
| Overall Survival | Time from randomization to death of any cause. | 2 years |