Phase II Evaluation of Adjuvant Palbociclib Versus Chemotherapy in Elderly Patients with High-Risk ER+/HER2- Localized Breast Cancer
- Trial ID
- 2023-505223-31-00
- Protocol
- EORTC-1745-ETF-BCG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of combining at least 5 years of endocrine therapy with 2 years of **palbociclib** as adjuvant systemic treatment, as an alternative to adjuvant chemotherapy followed by endocrine therapy, in older patients with pathologic stage III ER+/HER2- early breast cancer. This is clinically relevant as it explores a potentially less toxic and more tolerable treatment regimen for elderly patients, who may not tolerate traditional chemotherapy well.
Secondary objectives include:
- Evaluating the efficacy concerning different time-to-event endpoints such as distant recurrence-free interval (DRFI), breast cancer-specific survival (BCSS), and overall survival (OS) at 3, 6, and 10 years in both treatment arms.
- Assessing toxicity in both arms.
- Evaluating treatment discontinuation and dose reduction rates in both arms.
- Assessing the reasons for treatment discontinuation.
- Evaluating the completion of oral therapy in the experimental arm.
- Assessing the evolution of Health-Related Quality of Life (HRQoL) in both arms.
- Evaluating the evolution, prognostic, and predictive effects of geriatric assessment in both arms.
Participants
The clinical trial involves a total of **26 participants** diagnosed with **localized ER+ breast cancer**. The study population includes both **men and women** aged **70 years and older**, with a **WHO Performance status** ranging from 0 to 2, indicating a generally good health status. Participants were selected based on specific criteria, including having undergone breast surgery with curative intent and having no active wound healing complications. The trial excludes vulnerable populations. Lifestyle considerations such as the ability to swallow and retain oral medication are relevant, as participants must be able to adhere to the treatment regimen. The trial requires participants to have completed a G8 geriatric assessment and to consent to translational research, which includes sequential blood sampling. The study does not focus on any specific dietary or physical activity requirements. Key inclusion criteria include having adequate baseline organ function and a histologically confirmed diagnosis of ER+ and HER2-negative early invasive breast cancer. The trial does not provide information on specific lifestyle habits such as diet or exercise beyond the ability to manage oral medication.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **palbociclib** in combination with endocrine therapy as an adjuvant treatment for older patients with high-risk, estrogen receptor-positive (ER+), HER2-negative early breast cancer. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to compare the outcomes of patients receiving palbociclib and endocrine therapy against those receiving standard adjuvant chemotherapy followed by endocrine therapy. The trial is expected to run until October 2026, with recruitment having started in September 2019.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and surgical history. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of distant recurrence-free interval and overall survival. The primary endpoint is the 3-year distant recurrence-free interval rate in the experimental arm. Secondary endpoints include breast cancer-specific survival and overall survival at 3, 6, and 10 years, as well as adverse events and quality of life assessments.
The expected duration of participant involvement is up to 24 months for those in the palbociclib arm, with a maximum treatment period of 24 months for palbociclib and 120 months for endocrine therapy. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. Participants will also have an end-of-study visit to evaluate final outcomes and any long-term effects of the treatment.
Treatment
The clinical trial involves the administration of **IBRANCE** (palbociclib), an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, which is available in both hard capsule and film-coated tablet forms. The hard capsules are available in dosages of 75 mg, 100 mg, and 125 mg, while the film-coated tablets are available in the same dosages. The medication is administered orally, with a maximum daily dose of 125 mg and a total dose limit of 84,000 mg over a maximum treatment period of 24 months. The pharmaceutical form and dosage are selected based on the specific needs of the trial protocol, and participant compliance is monitored throughout the study.
**Exemestane** is utilized as a non-experimental treatment in this trial. It is a steroidal aromatase inhibitor available in coated tablet form, administered orally at a maximum daily dose of 25 mg. The total dose can reach up to 84,000 mg over a treatment period of up to 120 months. This medication serves as a comparator in the study, providing a standard-of-care reference for evaluating the efficacy of the experimental treatment.
**Epirubicin hydrochloride** is included as a comparator treatment, classified under anthracyclines. It is provided as a solution for injection or infusion, administered intravenously. The maximum daily dose is 90 mg/m², with a total dose limit of 360 mg/m² over a 12-month period. This treatment is used to compare the effects of the experimental medication against a well-established chemotherapy agent.
**Anastrozole** is another non-experimental treatment used in the trial, functioning as a non-steroidal aromatase inhibitor. It is available in film-coated tablet form, administered orally at a maximum daily dose of 1 mg, with a total dose limit of 3,360 mg over 120 months. This medication is used as a comparator to assess the relative efficacy of the experimental treatment.
**Doxorubicin**, also an anthracycline, is provided as a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 60 mg/m², with a total dose limit of 240 mg/m² over a 12-month period. This treatment serves as a comparator, offering a benchmark for evaluating the experimental treatment's performance.
**Paclitaxel** is included as a cytostatic agent, available as a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 80 mg/m², with a total dose limit of 960 mg/m² over 12 months. This treatment is used to compare the experimental medication's efficacy against a standard chemotherapy regimen.
**Letrozole** is utilized as a non-steroidal aromatase inhibitor, available in film-coated tablet form, administered orally at a maximum daily dose of 2.5 mg. The total dose can reach up to 8,400 mg over a treatment period of up to 120 months. This medication serves as a comparator in the study, providing a standard-of-care reference for evaluating the efficacy of the experimental treatment.
**Docetaxel** is another cytostatic agent, provided as a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 75 mg/m², with a total dose limit of 300 mg/m² over a 12-month period. This treatment serves as a comparator, offering a benchmark for evaluating the experimental treatment's performance.
**Cyclophosphamide** is included as a cytostatic agent, available as a powder for solution for injection or infusion, administered intravenously. The maximum daily dose is 600 mg/m², with a total dose limit of 2,400 mg/m² over 12 months. This treatment is used to compare the experimental medication's efficacy against a standard chemotherapy regimen.
**Tamoxifen** is utilized as an antioestrogen, available in tablet form, administered orally at a maximum daily dose of 20 mg. The total dose can reach up to 67,200 mg over a treatment period of up to 120 months. This medication serves as a comparator in the study, providing a standard-of-care reference for evaluating the efficacy of the experimental treatment.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the 3-year distant recurrence-free interval rate in the experimental arm. Secondary endpoints include the distant recurrence-free interval at 3 years in the control arm and at 6 and 10 years in both arms, breast cancer-specific survival at 3, 6, and 10 years in both arms, and overall survival at 3, 6, and 10 years in both arms. Additionally, adverse events will be recorded according to CTCAE v5.0 at every patient visit in both arms, and treatment discontinuation and dose reduction rates will be monitored. The reasons for treatment discontinuation will also be documented.
Patient-reported outcomes will be evaluated using HRQoL questionnaires, including the modified QLQ-C30, ELD-14, and selected items from the BR45 module, at 3 months, 6 months, 1 year, 2 years, and 3 years in both arms. Geriatric assessment tools such as G8, iADL, ADL, Gait speed, CCI, and social situation will be utilized at the same timepoints. These assessments will provide comprehensive data on the efficacy of the treatment regimen involving **palbociclib** as an adjuvant systemic treatment in elderly patients with high-risk ER+/HER2- early breast cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Women or men with pathologic stage II or stage III, early invasive breast cancer according to the UICC 8th edition for TNM classification
- Patient must have undergone breast +/- axillary surgery with curative intent for the current malignancy ≤12 weeks before randomization. The final primary tumor surgical specimen must have R0 margins free from tumor.
- 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.
- Incentive to undergo adjuvant radiation therapy when indicated per local institutional guidelines. Note: For patients in the palbociclib arm, radiation therapy when indicated has to start ≤13 weeks after last surgery. The endocrine therapy can be initiated during or after the radiation therapy but not later than 4 weeks after the last radiotherapy. Palbociclib has to start ≤4 weeks after the last radiotherapy. When radiation therapy is not indicated, endocrine therapy and palbociclib have to be initiated ≤13 weeks after last surgery. Note: For patients in the chemotherapy arm, chemotherapy has to be the first adjuvant treatment and has to start ≤ 13 weeks after the last surgery. When radiation therapy is indicated, this treatment has to start ≤9 weeks after the last chemotherapy administration. Adjuvant endocrine therapy can be initiated during or after the radiation therapy but not later than 4 weeks after the last radiotherapy. When radiation therapy is not indicated, endocrine therapy has to be initiated ≤6 weeks after last chemotherapy administration.
- Adequate baseline organ function, evidenced by the following laboratory results within 3 weeks of randomization: - Hemoglobin ≥ 9 g/dL - Absolute neutrophil count (ANC) ≥ 1500/mm3 - Platelet count ≥ 100,000/mm3 - Total bilirubin ≤ 1.5 upper limit of normal (ULN), or total bilirubin ≤ 3.0 ×ULN in patients with documented Gilbert's Syndrome. - Glomerular Filtration Rate (GFR) ≥ 30 ml/min according to MDRD formula or CKD-EPI formula or Cockcroft and Gault formula - SGOT (AST), SGPT (ALT) and alkaline phosphatase ≤ 2.5 × ULN
- For men participating in the trial: • As fertility may be affected permanently with protocol treatment, we advise offering to patient sperm preservation prior to treatment. • With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive** method that together result in a failure rate of <1% per year during the treatment period and for 6 months after the last dose of chemotherapies or 3 months and half (14 weeks) after the last dose of palbociclib. Men must refrain from donating sperm during the same period. • With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of chemotherapies or 3 months and half (14 weeks) after last dose of palbociclib to avoid exposing the embryo. ** For female partner, a highly effective method of birth control includes: • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) • Intrauterine device (IUD) • Intrauterine hormone-releasing system (IUS) • Bilateral tubal occlusion • Vasectomized partner • Sexual abstinence
- Signed, written informed consent.
- Histologically confirmed ER+ (at least 10 % of cells staining positive for ER), HER-2 negative, early invasive breast cancer based on results of local pathology. Testing may be performed on diagnostic core biopsy or resection specimen.
- In patients with multicentric, multifocal and/or bilateral breast cancer, all histopathologically examined invasive tumors must meet pathologic criteria regarding ER and HER2-status described above.
- Adjuvant chemotherapy indicated and feasible according to treating physician and patient, based on standard clinicopathological parameters (tumor size, lymph node involvement, general health status, proliferation marker, patient wish) and gene expression profile if available.
- Adjuvant chemotherapy with both anthracycline and taxanes (in combination or in sequence) considered not indicated or not feasible according to treating physician.
- Age ≥70 years
- WHO Performance status 0-2
- Completed G8 geriatric assessment within 3 weeks of randomization
- Participation in translational research is mandatory and therefore patient must consent for it. Patient should allow sequential sampling of blood during the course of the trial
- Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
Exclusion Criteria
- Evidence of macroscopic distant metastases, investigated according to local institutional guidelines
- History of extensive disseminated/bilateral or known presence of interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis, but not history of prior radiation pneumonitis.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (including known HIV, active hepatitis B and/or hepatitis C infection), symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or uncontrolled diabetes. Note: For patients for whom doxorubicin or epirubicin is planned, an adequate baseline cardiac function (left ventricular ejection fraction ≥ 50%) should have been proven no more than 1 year before treatment start.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- Other malignancy within the last 5 years except: adequately treated non-metastatic non-melanoma skin cancer, or successfully treated in situ carcionoma for example curatively treated in situ cancer of the cervix, ductal carcinoma in situ of the breast.
- Previous history of invasive breast cancer
- Systemic anticancer therapy prior to the breast cancer surgery
- Prior therapy with any CDK4/6 inhibitor
- Concurrent investigational agent within 28 days of randomization or five elimination half-lives, whichever is longer
- Concomitant anticancer treatment with the exception of bone antiresorptive agents or LHRH agonists in male patients treated with an aromatase-inhibitor
- History of allergic reactions attributed to compounds of chemical or biological composition similar to palbociclib or to chemotherapy components
- Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption
- Medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization
- Patients who received treatment with live vaccines within 30 days prior the first dose of study medication.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 18 Sept 2019 | 56 |
 France | Not Recruiting | 18 Sept 2019 | 164 |
 Germany | Not Recruiting | 18 Sept 2019 | 30 |
 Italy | Not Recruiting | 18 Sept 2019 | 28 |
 Poland | Not Recruiting | 18 Sept 2019 | 2 |
 Portugal | Not Recruiting | 18 Sept 2019 | 7 |
 Spain | Not Recruiting | 18 Sept 2019 | 60 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IBRANCE 75 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 75 | 24 | PRD6503939 |
EXEMESTANE | Other | — | ORAL USE | 25 | 120 | SUB07492MIG |
IBRANCE 125 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 125 | 24 | PRD6503994 |
IBRANCE 100 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 100 | 24 | PRD6503933 |
IBRANCE 75 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 75 | 24 | PRD8174762 |
IBRANCE 125 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 125 | 24 | PRD6503998 |
IBRANCE 75 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 75 | 24 | PRD7907996 |
TAMOXIFEN | Other | — | ORAL USE | 20 | 120 | SUB10825MIG |
IBRANCE 75 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 75 | 24 | PRD7907995 |
IBRANCE 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 100 | 24 | PRD7907867 |