PAlbociclib Plus Tamoxifen for the Treatment of Hormone Receptor-positive, HER2-negative Advanced Breast Cancer Women - Asian studY

Study Overview
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Brief Summary
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This study is conducted to evaluate the benefit of adding palbociclib in hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer patients, regardless of menopausal status, treated with tamoxifen (with or without goserelin) versus tamoxifen alone (with or without goserelin).

Official Title
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Asian, International, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Tamoxifen With or Without Palbociclib ± Goserelin in Women With Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Placebo
* Drug: Tamoxifen
* Drug: Goserelin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women 18 years of age or older with histologically or cytologically proven locally advanced or metastatic breast cancer, not amenable to resection or radiation therapy with curative intent Documented diagnosis of HR+/HER2- breast cancer Any menopausal status Previously untreated with any endocrine therapy for their HR+/HER2- advanced breast cancer; or progressed while on or within 3 month from prior endocrine therapy other than tamoxifen for advanced breast cancer. If patients have adjuvant endocrine therapy, they must satisfy as follows: progressed 12 months or more since prior adjuvant endocrine therapy with tamoxifen; or progressed during or after adjuvant endocrine therapy with an aromatase inhibitor. Measurable disease or non-measurable disease as defined by RECIST ver.1.1 Eastern Cooperative Oncology Group (ECOG) PS 0-1 Adequate organ and marrow function, resolution of all toxic effects of prior therapy or surgical procedures Exclusion Criteria: Prior treatment with any CDK inhibitor, tamoxifen, everolimus, or agent that inhibits the PI3K-mTOR pathway Patients with extensive advanced/metastatic, symptomatic visceral disease, or known uncontrolled or symptomatic CNS metastases Use of strong or moderate CYP3A4 and/or CYP2D6 inhibitors or inducers Major surgery or any anti-cancer therapy within 2 weeks of randomization Prior stem cell or bone marrow transplantation

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib + Tamoxifen ± Goserelin<br>Palbociclib 125 mg/day, orally once daily on Day 1 to Day 21 followed by 7 days off treatment for each 28 day cycle, plus tamoxifen 20 mg orally once daily (continuously) | Drug: Palbociclib<br>* Palbociclib, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>* Other names: PD-0332991;Drug: Tamoxifen<br>* Tamoxifen, 20mg, orally once daily (continuously)<br>Drug: Goserelin<br>* For pre/perimenopausal patients only: Goserelin, 3.6 mg, subcutaneously every 4 weeks; or 10.8 mg, subcutaneously every 12 weeks<br>|
| Active Comparator: Placebo + Tamoxifen ± Goserelin<br>Placebo orally once daily on Day 1 to Day 21 followed by 7 days off treatment for each 28 day cycle, plus tamoxifen 20 mg orally once daily (continuously) | Drug: Placebo<br>* Placebo, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Tamoxifen<br>* Tamoxifen, 20mg, orally once daily (continuously)<br>Drug: Goserelin<br>* For pre/perimenopausal patients only: Goserelin, 3.6 mg, subcutaneously every 4 weeks; or 10.8 mg, subcutaneously every 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The time from the date of randomization to the date of the first documentation of objective progression of disease (PD), clinically diagnosed symptomatic deterioration, or death due to any cause in the absence of documented PD, whichever occurs first. | Baseline up to 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The time from date of randomization to date of death due to any cause. | From the randomization of the last patient up to 3 years | 
| Survival Probabilities at 1 year, 2 year, and 3 year | The probability of survival 1 year, 2 or 3 years after the date of randomization based on the Kaplan-Meier estimate. | From the randomization of the last patient up to 3 years | 
| Objective Response (OR) | Complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) ver.1.1 recorded from randomization until disease progression or death due to any cause. | Baseline up to 3.5 years | 
| Duration of Response (DR) | The time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. | Baseline up to 3.5 years | 
| Clinical Benefit Response (CBR) | CR or PR or SD >=24 weeks according to the RECIST version 1.1 recorded in the time period between randomization and disease progression or death of any cause. | Baseline up to 3.5 years | 
| Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher change in scores from baseline is considered clinically significant. | Baseline up to 3.5 years | 
| Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from 'not at all' to 'very much'. All scores are converted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning. | Baseline up to 3.5 years | 
| Trough plasma concentrations of palbociclib | Ctrough for palbociclib | Cycle 1/Day 15 and Cycle 2/Day 15 | 
| Trough plasma concentrations of tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen and endoxifen | Ctrough for tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen and endoxifen | Cycle 2/Day 15 and Cycle 3/Day 15 | 
| Treatment-Emergent Adverse Events |  | From the first dose of the investigational product until 28 days after the last dose of study drugs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast Cancer, palbociclib (PD-0332991), tamoxifen, goserelin, any menopausal status, hormone receptor positive, HER2 negative, locally advanced, metastatic