PALbociclib CoLlaborative Adjuvant Study

Study Overview
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Brief Summary
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This is a prospective, two arm, international, multicenter, randomized, open-label Phase III study evaluating the addition of 2 years of palbociclib to standard adjuvant endocrine therapy for patients with HR+ / HER2- early breast cancer (EBC). The purpose of the PALLAS study is to determine whether the addition of palbociclib to adjuvant endocrine therapy will improve outcomes over endocrine therapy alone for HR+/HER2- early breast cancer. Assessment of a variety of correlative analysis, including evaluation of the effect of palbociclib in genomically defined tumor subgroups, is planned.

Official Title
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PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive (HR+) / Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Early Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Standard Adjuvant Endocrine Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to study specific procedures. Age ≥18 years (or per national guidelines). Pre- and postmenopausal women or men with Stage II (Stage IIA limited to max. 1000 patients) or Stage III early invasive breast cancer Patients with multicentric and/or multifocal and/or bilateral early invasive breast cancer are eligible if all histopathologically examined tumors meet pathologic criteria for ER+ and/or PR+ and HER2-. Patients must have histologically confirmed ER+ and/or PR+, HER2-, early invasive breast cancer. Patients must have undergone adequate (definitive) breast surgery for the current malignancy. FFPE tumor tissue block must be confirmed to be received at the central sample repository prior to randomization. ECOG performance status 0-1. Patients must be able and willing to swallow and retain oral medication. Serum or urine pregnancy test must be negative in premenopausal women within 14 days of randomization, or in women with amenorrhea of less than 12 months at time of randomization. Patients who received neo/adjuvant therapy must be after last dose of chemotherapy and/or biologic therapy and must have sufficient resolution of side effects. Patients who received breast/axilla/post-mastectomy chest wall radiotherapy must be after last dose of radiotherapy and must have sufficient resolution of side effects. Patients must have sufficient resolution of any surgical side effects (no active wound healing complications). -Patients must either be initiating or have already started adjuvant hormonal treatment. - Patients who already received neo/adjuvant endocrine therapy are eligible as long as they are enrolled within 12 months of initial histological diagnosis and after completing no more than 6 months of adjuvant endocrine therapy. Absolute neutrophil count ≥ 1,500/µL Platelets ≥ 100,000/ mm3 Hemoglobin ≥ 10g/dL Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome. Aspartate amino transferase (AST or SGOT) and alanine amino transferase (ALT or SGPT) ≤ 1.5 × institutional ULN. Serum creatinine below the upper limit of the institutional normal range (ULN) or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN. Exclusion Criteria: Concurrent therapy with other Investigational Products. Prior therapy with any CDK inhibitor. Patients with Stage I or IV breast cancer are not eligible. History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib. Patients receiving any medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization. Uncontrolled intercurrent illness that would limit compliance with study requirements. Pregnant women, or women of childbearing potential without a negative pregnancy test within 14 days prior to randomization. Patients with a history of any malignancy are ineligible Patients who previously received endocrine therapy within 5 years prior to diagnosis of the current malignancy. Patients on antiretroviral therapy. Patients with clinically significant history of any chronic liver disease. Patients receiving concurrent exogenous hormone therapy (topical vaginal estrogen therapy is allowable).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Experimental: Arm A<br>Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years. | Drug: Palbociclib<br> <br> Drug: Standard Adjuvant Endocrine Therapy<br> <br> |
| Other: Arm B<br>Standard adjuvant endocrine therapy for a duration of at least 5 years. | Drug: Standard Adjuvant Endocrine Therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease Free Survival (iDFS) | Invasive disease-free survival (iDFS) for the combination of at least 5 years endocrine therapy and 2-year palbociclib treatment versus at least 5 years endocrine therapy alone in patients with histologically confirmed HR+/HER2- invasive early breast cancer (EBC) at 4 years. iDFS is defined as the time from randomization to the date of the first event: local/regional invasive ipsilateral recurrence, contralateral invasive breast cancer, distant recurrence, second primary invasive cancer of non-breast origin or death from any cause. Direct comparison between arms used time to iDFS events and Kaplan-Meier Log-rank analysis. Due to the medians not yet achieved, the percentage of patients considered iDFS at 4 years is reported. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease Free Survival (iDFS) Excluding Second Primary Invasive Cancers of Non-breast Origin. | Invasive disease-free survival (iDFS, excluding second primary invasive cancers of non-breast origin) for the combination of at least 5 years endocrine therapy and 2-year palbociclib treatment versus at least 5 years endocrine therapy alone in patients with histologically confirmed HR+/HER2- invasive early breast cancer (EBC) at 4 years. iDFS excluding second primary invasive cancers of non-breast origin is defined as the time from randomization to the date of the first event: local/regional invasive ipsilateral recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause. Second primary invasive cancers of non-breast origin will not be considered as events for this endpoint. Direct comparison between arms used time to iDFS events and Kaplan-Meier Log-rank analysis. Due to the medians not yet achieved, the percentage of patients considered iDFS at 4 years is reported. | 4 years | 
| Distant Recurrence-free Survival (DRFS) | Compare time to distant recurrence-free survival (DRFS). Distant recurrence is defined according to STEEP criteria as the time from randomization to the date of the first event: distant recurrence or death from any cause. Patients with a locoregional recurrence will continue to be followed for DRFS. Surviving patients who are event-free will be censored at: the date of last disease assessment, or withdrawal of consent to be followed, or death whichever came first. Direct comparison between arms used time to DRFS events and Kaplan-Meier Log-rank analysis. Due to the medians not yet achieved, the percentage of patients considered DRFS at 4 years is reported. | 4 years | 
| Overall Survival (OS) | Compare overall survival (OS). Overall survival is defined as the time period between randomization and death. Surviving patients classified as lost-to-follow up or having withdrawn consent to be followed will be censored at their date of last contact or withdrawal of consent to be followed, whichever occurs first. | 4 years | 
| Locoregional Recurrences-free Survival (LRRFS) | Compare locoregional recurrence-free survival (LRRFS). LRRFS is defined as the time from randomization to the date of the first event: local/regional invasive ipsilateral recurrence, contralateral invasive breast cancer, or death from any cause. Patients with second primary invasive cancers of non-breast origin or distant recurrence will be censored at the date of diagnosis. Surviving patients who are event-free will be censored at: the date of last disease assessment, or withdrawal of consent to be followed, whichever occurs first. | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HR+/HER2- breast cancer, Palbociclib