Phase III Randomized Trial of Palbociclib Plus Endocrine Therapy Versus Endocrine Therapy Alone in HR+/HER2- Early Breast Cancer

Trial ID: 2024-514841-12-00
Protocol: AFT-05/ABCSG-42/BIG_
Sponsor: Alliance Foundation Trials LLC

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Diseases & Conditions

Hormone receptor positive breast cancer

Objectives

The primary objective of this study is to compare **invasive disease-free survival (iDFS)** in patients with histologically confirmed hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer. The comparison is between a treatment regimen of at least 5 years of endocrine therapy combined with a 2-year course of **palbociclib** versus at least 5 years of endocrine therapy alone. This objective is clinically relevant as it aims to determine whether the addition of palbociclib can enhance the efficacy of standard adjuvant endocrine therapy, potentially leading to improved patient outcomes in terms of disease recurrence.

Secondary objectives include: - Comparing endpoints such as iDFS excluding second primary invasive cancers of non-breast origin, distant recurrence-free survival (DRFS), locoregional recurrences-free survival (LRRFS), and overall survival (OS). - Evaluating the safety profile of a 2-year palbociclib treatment in combination with adjuvant endocrine therapy versus adjuvant endocrine therapy alone. These secondary objectives are crucial for understanding the broader impact of palbociclib on survival outcomes and its safety when used in conjunction with standard endocrine therapy.

Participants

The clinical trial involves a total of **4094 participants** diagnosed with **hormone receptor-positive (HR+) and HER2-negative early invasive breast cancer**. The study population includes both premenopausal and postmenopausal women, as well as men, aged **18 years and older**. Participants are required to have undergone adequate breast surgery for their current malignancy and must have histologically confirmed HR+ and HER2- status. The trial includes individuals with Stage II or Stage III early invasive breast cancer, with a maximum of 1000 patients in Stage IIA. Both genders are represented in the study, and the trial population was selected based on specific inclusion criteria, such as the ability to swallow and retain oral medication and an **ECOG performance status** of 0-1. Participants may have received prior neo/adjuvant therapy, but must have sufficient resolution of side effects. Lifestyle considerations, such as diet and physical activity, are not specified. The trial also includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants. The study aims to evaluate the efficacy of adding palbociclib to adjuvant endocrine therapy compared to endocrine therapy alone.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **palbociclib** in combination with standard adjuvant endocrine therapy compared to standard adjuvant endocrine therapy alone in patients with hormone receptor-positive (HR+)/HER2-negative early breast cancer. This is a randomized, phase III, double-blind, controlled trial. The primary objective is to compare invasive disease-free survival (iDFS) between the two treatment arms. The trial is expected to run until December 31, 2028, with recruitment having started on October 28, 2015.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, medical history, and laboratory values. Key inclusion criteria include a histologically confirmed diagnosis of HR+/HER2- early invasive breast cancer, adequate organ function, and the ability to swallow oral medication. Exclusion criteria are not specified in the provided data. Following the screening, participants will be randomized to receive either the combination therapy or standard therapy alone.

Study visits will occur at regular intervals to monitor the participants' health, adherence to the treatment regimen, and any adverse events. These visits will include assessments such as physical examinations, laboratory tests, and imaging studies as needed. The end-of-study visit will mark the conclusion of the participant's involvement in the trial, where final evaluations will be conducted to assess the outcomes of the treatment.

The expected length of participant involvement is up to 52 weeks of treatment with **palbociclib**, in addition to at least five years of endocrine therapy. Participants may be withdrawn from the study early due to reasons such as significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide valuable data on the potential benefits of adding **palbociclib** to standard endocrine therapy in improving outcomes for patients with early breast cancer.

Treatment

The clinical trial involves the administration of **Palbociclib**, a chemical-origin medication, in the form of capsules. The active substance, palbociclib, is provided by ABCSG GMBH. The pharmaceutical form is capsules, and the medication is identified by the sponsor product code PD-0332991. The maximum daily dose of palbociclib is 125 mg, with a total maximum dose of 68,250 mg over the treatment period. The treatment duration is set for a maximum of 52 weeks. The route of administration is oral, and the medication is not formulated for pediatric use. Palbociclib is not classified as an orphan drug in this study.

In addition to the experimental treatment with palbociclib, participants will receive standard adjuvant endocrine therapy as part of the study protocol. This standard-of-care therapy is administered to all participants, serving as a comparator to evaluate the efficacy of the combination treatment. The trial aims to compare invasive disease-free survival between the combination of palbociclib with endocrine therapy and endocrine therapy alone in patients with hormone receptor-positive, HER2-negative early breast cancer. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the evaluation of **invasive disease-free survival (iDFS)**, defined according to the STEEP criteria. This primary endpoint will measure the time from randomization to the first occurrence of invasive breast cancer recurrence, a second primary invasive cancer, or death from any cause. Secondary endpoints include iDFS excluding second primary invasive cancers of non-breast origin, overall survival (OS), locoregional recurrences-free survival (LRRFS), distant recurrence-free survival (DRFS), and adverse events. These endpoints will provide a comprehensive assessment of the treatment's impact on disease progression and patient survival.

The trial will involve the administration of **Palbociclib** in combination with standard adjuvant endocrine therapy, compared to standard adjuvant endocrine therapy alone, in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. The treatment period for Palbociclib is set for 2 years, alongside at least 5 years of endocrine therapy. The efficacy parameters will be collected and analyzed at various time points throughout the study, with the estimated end date set for December 31, 2028. The trial aims to provide robust data on the efficacy of Palbociclib in improving survival outcomes in this patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

(1) Signed informed consent obtained prior to any study specific assessments and procedures.
(2) Age ≥18 years (or per national guidelines).
(3) Premenopausal and postmenopausal women or men with Stage II (Stage IIA limited to a max. of 1000 patients) or Stage III early invasive breast cancer per AJCC Breast Cancer Staging version 7 /UICC . Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice.
(4) Patients with multicentric and/or multifocal and/or bilateral early invasive breast cancer whose histopathologically examined tumors all meet pathologic criteria for ER+ and/or PR+ and HER2-.
(5) Patients must have histologically confirmed hormone receptor positive (ER+ and/or PR+), HER2-, early invasive breast cancer. ER, PR and HER2 measurements should be performed acc. to institutional guidelines, in a CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP guidelines. Patients with equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines are eligible, as long as they have not received and are not scheduled to receive anti-HER2 treatment. Testing may occur on diagnostic core or surgical tumor tissue.
(6) Patients must have undergone adequate (definitive) breast surgery for the current malignancy.
(7) A formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be transmitted to a central sample repository and confirmation of receipt must be available prior to randomization.
(8) ECOG performance status 0-1.
(9) Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
(10) Serum or urine pregnancy test must be negative within 7 days of randomization in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male patients randomized into treatment Arm A or B must use adequate contraception for the duration of protocol treatment and for 6 months after the last treatment with palbociclib if they are in arm A. In addition, patients receiving standard adjuvant endocrine therapy (Arm A and Arm B) should use adequate contraception in accordance with the specific medication requirements (e.g. SmPC).
(11) Patients may or may not have received neo/adjuvant therapy, but must be after last dose of chemotherapy and/or biologic therapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
(12) Patients may or may not have received breast/axilla/postmastectomy chest wall radiotherapy, but must be after last dose of radiotherapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
(13) Patients must have sufficient resolution of any surgical side effects from the last surgery per physician assessment with no active wound healing complications at the time of randomization.
(14) Patients must either be initiating or have already started adjuvant hormonal treatment. Patients may already have initiated endocrine therapy at the time of randomization, but randomization must take place within 12 months of date of histological diagnosis and within 6 months of initiating standard adjuvant endocrine therapy. Patients who received neoadjuvant endocrine therapy are eligible as long as they are randomized within 12 months of initial histological diagnosis and after completing no more than 6 months of adjuvant endocrine therapy. Patients may be receiving either tamoxifen or aromatase inhibitor (AI: letrozole, anastrozole, or exemestane). For premenopausal patients and men, concurrent LHRH agonist use is allowable and may also be ongoing at the time of randomization. If a LHRH agonist was used for ovarian protection during neo/adjuvant chemotherapy it is allowable and shall not be taken into account for calculations regarding the 6 months standard adjuvant endocrine therapy.
(15) Absolute neutrophil count ≥ 1,500/mm3
(16) Platelets ≥ 100,000/ mm3
(17) Hemoglobin ≥ 10g/dL
(18) Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome.
(19) Aspartate amino transferase (AST or SGOT) and alanine amino transferase (ALT or SGPT) ≤ 1.5 × institutional ULN.
(20) Serum creatinine below the upper limit of the institutional normal range (ULN) or creatinine clearance (or glomerular filtration rate [GFR]) ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN.

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Exclusion Criteria

(1) Concurrent therapy with other Investigational Products.
(2) Prior therapy with any CDK inhibitor.
(3) Patients with Stage I or IV breast cancer are not eligible. Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice.
(4) History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
(5) Patients receiving any medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization.
(6) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
(7) Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
(8) Patients with a history of any malignancy are ineligible except for the following circumstances: • Patients with a malignancy history other than invasive breast cancer are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. • Patients with the following cancers are eligible, even if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and non-metastatic non-melanomatous skin cancer.
(9) Patients are not eligible if they have previously received endocrine therapy within 5 years prior to diagnosis of the current malignancy. This includes use for prophylactic reasons, including treatment of osteoporosis or cancer prevention with tamoxifen, raloxifene or AI. Patients may concurrently receive bisphosphonates or rank ligand inhibitors while on this study if necessary for treatment or prevention of osteopenia or osteoporosis.
(10) Patients on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
(11) Patients with clinically significant history of chronic liver disease, including chronic/active viral or other known hepatitis, current alcohol abuse, or cirrhosis, etc.
(12) Patients receiving concurrent exogenous hormone therapy (hormone replacement therapy, oral or any other hormonal contraceptives such as hormonal contraceptive coil, etc.) are not eligible but topical vaginal estrogen therapy is allowable.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	28 Oct 2015	479
Belgium	Not Recruiting	28 Oct 2015	119
Germany	Not Recruiting	28 Oct 2015	138
Hungary	Not Recruiting	28 Oct 2015	145
Ireland	Not Recruiting	28 Oct 2015	148
Italy	Not Recruiting	28 Oct 2015	106
The Netherlands	Not Recruiting	28 Oct 2015	—
Poland	Not Recruiting	28 Oct 2015	105
Portugal	Not Recruiting	28 Oct 2015	84
Spain	Not Recruiting	28 Oct 2015	1001