Efficacy and Safety of Palbociclib and Fulvestrant in HR+/HER2- Advanced Breast Cancer Post-CDK4/6 Inhibitor Therapy: A Phase II Multicenter Study
- Trial ID
- 2024-513372-18-00
- Protocol
- GIM24-PALBO-BP
- Sponsor
- Consorzio Oncotech
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and safety of the combination of palbociclib and fulvestrant in women with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (LABC or MBC) who have experienced disease progression following treatment with a CDK4/6 inhibitor in combination with hormonal therapy. This evaluation is clinically relevant as it aims to provide insights into the potential benefits of this therapeutic regimen in a patient population with limited treatment options after the failure of previous therapies.
Secondary objectives include assessing predictive biomarkers of response or resistance to the combination of fulvestrant and palbociclib using metastatic tumor tissue samples and liquid biopsies. Identifying these biomarkers is crucial for understanding the mechanisms of action and resistance, potentially guiding personalized treatment strategies in the future.
Participants
The clinical trial involves a study population of **pre- and post-menopausal women** aged 18 years and older, diagnosed with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). The total number of participants is not provided by the sponsor. Participants were selected based on their disease progression following treatment with a CDK4/6 inhibitor in combination with hormonal therapy, either in the adjuvant or metastatic setting. The trial specifically targets women who have relapsed at least 12 months after the last CDK4/6 dosage in the adjuvant setting or have shown progression from a first-line combined hormonal treatment for metastatic disease. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include histological confirmation of ER and/or PgR ≥ 1% and HER2-negative breast cancer, adequate bone marrow and organ function, and an estimated life expectancy of more than 12 weeks. The trial does not include male subjects or vulnerable populations.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **palbociclib** in combination with fulvestrant in women with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (LABC or MBC) who have previously been treated with a CDK4/6 inhibitor in combination with hormonal therapy. This is a multicenter, phase II trial with a randomized, double-blind, controlled design. The trial is expected to run until December 31, 2026, with recruitment having started on October 18, 2019.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, menopausal status, and previous treatment history. The inclusion criteria require participants to be adult women with LABC or MBC, not amenable to curative treatment by surgery or radiotherapy, and who have progressed on a CDK4/6 inhibitor in combination with an aromatase inhibitor or tamoxifen. Participants must have relapsed at least 12 months after the last CDK4/6 dosage in the adjuvant setting or at progression from a first-line combined hormonal treatment for metastatic disease. Additionally, participants must provide written informed consent and meet specific health and laboratory criteria.
Following the screening visit, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of overall response rate, progression-free survival, and overall survival. The primary endpoints focus on evaluating the efficacy of the combination treatment, while secondary endpoints aim to assess predictive biomarkers of response or resistance using metastatic tumor tissue samples and liquid biopsies. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and any long-term effects of the treatment.
The expected length of participant involvement is up to 18 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants may also be withdrawn if they do not comply with the study protocol or if the investigator deems it in their best interest. The trial aims to provide valuable insights into the treatment of HR+/HER2- LABC or MBC, potentially improving therapeutic strategies for this patient population.
Treatment
The clinical trial involves the administration of **palbociclib**, a **CDK4/6 inhibitor**, as the experimental medication. The study utilizes several formulations of palbociclib, including IBRANCE 125 mg hard capsules, IBRANCE 125 mg film-coated tablets, IBRANCE 100 mg film-coated tablets, IBRANCE 100 mg hard capsules, IBRANCE 75 mg hard capsules, and IBRANCE 75 mg film-coated tablets. Each formulation contains the active substance palbociclib, which is of chemical origin. The pharmaceutical forms include hard capsules and film-coated tablets, all intended for oral administration. The maximum daily dose for the 125 mg formulations is 125 mg, while for the 100 mg and 75 mg formulations, it is 100 mg and 75 mg, respectively. The maximum treatment period for all formulations is 18 cycles, with each cycle lasting 28 days.
In addition to the experimental medication, the study may involve the use of standard-of-care therapy, which includes hormonal therapy such as aromatase inhibitors or tamoxifen, with or without LHRHa, as previously administered to participants. The trial does not include a placebo or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial aims to evaluate the efficacy and safety of palbociclib in combination with fulvestrant in women with hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, who have previously been treated with a CDK4/6 inhibitor in combination with hormonal therapy.
Efficacy
The efficacy of the clinical trial will be assessed using several primary endpoints, including the overall response rate (ORR), **Progression-Free Survival (PFS)**, 6-month PFS rate, and overall survival (OS). These parameters will be evaluated to determine the effectiveness of the combination of fulvestrant and palbociclib in patients who have progressed after a combined treatment of hormonal therapy and CDK4/6 inhibitors. The trial will also assess safety and tolerability as part of the primary endpoints.
Secondary endpoints will focus on assessing predictive biomarkers of response or resistance to the treatment using metastatic tumor tissue samples and liquid biopsies. The collection and analysis of these samples will provide insights into the biological mechanisms underlying treatment response and resistance.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult (>=18 years of age) pre or post-menopausal women with LABC or MBC not amenable to curative treatment by surgery or radiotherapy, progressing to a CDK4/6 inhibitor in combination with aromatase inhibitor or tamoxifen in the adjuvant or metastatic setting. To be enrolled in the present trial patients must have relapsed at least after 12 months from the last CDK4/6 dosage in the adjuvant setting or at progression from a first line combined hormonal treatment for metastatic disease with a CDK4/6 inhibitor plus AI or Tam with duration of, at least, 6 months. For metastatic disease, patients must have achieved, at least a stable disease while the first line hormonal treatment with a CDK4/6 inhibitor plus AI or Tam to be enrolled in the trial.
- Patients receiving up to one line of chemotherapy before the first line hormonal treatment with a CDK4/6 inhibitor for metastatic disease may be enrolled in the study.
- Histological confirmation of ER and/or PgR >= 1% and HER2 negative breast cancer (IHC status 0, 1+, 2+ and FISH not amplified).
- Premenopausal women: in order to be eligible must have achieved surgical menopause with bilateral oophorectomy or ovarian radiation or medical menopause by treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (LHRHa) for induction of ovarian suppression.
- Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrollment
- Patients who received <= 28 days of fulvestrant for second line advanced breast cancer treatment prior to study enrollment are eligible.
- Patients must have: - At least one lesion that can be accurately measured in at least one dimension >= 20 mm with conventional imaging techniques or >= 10 mm with spiral CT or MRI - Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above.
- Adequate bone marrow and coagulation and adequate organ function defined as follows: - ANC > 1,000/mm3 (1.0 x 109/L); - Platelets > 75,000/mm3 (75 x 109/L); - Hemoglobin >= 9 g/dL (90 g/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 (<2.5 ULN if Gilbert’s disease); - AST and/or ALT <= 3 x ULN (<= 5 x ULN if liver metastases present); - Alkaline phosphatase <= 2.5 x ULN (<= 5 x ULN if bone or liver metastases present); - ECOG Performance Status <= 2; - Resolution of all acute toxic effects of prior therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade <=1 (except alopecia).
- Estimated life expectancy > of 12 weeks.
- Patients must perform liquid biopsy at study entry and at disease progression. Tissue biopsy of the most accessible metastatic site at study entry and at disease progression are required but not mandatory.
- Written informed consent obtained before any screening procedure and according to local guidelines.
Exclusion Criteria
- HER2-overexpressing patients by local laboratory testing (IHC3+ staining or in situ hybridization positive).
- Patients who received > 1 line of chemotherapy as treatment for MBC.
- Patients who received > 1 line of a CDK4/6 inhibitor in combination with hormonal treatment for LABC or MBC or who have relapsed at less than 12 months from the end of adjuvant treatment with a CDK4/6 inhibitor. For metastatic disease, patients with a progressive disease within the first 6 months of treatment while on first line therapy with a CDK4/6 inhibitor, will be excluded.
- Patients receiving chemotherapy or any type of hormonal therapy after treatment with a CDK4/6 inhibitor for metastatic disease.
- Patients interrupting the previous treatment with CDK4/6 inhibitor for cardiac and/or hepatic toxicity and not for disease progression.
- Pregnant, lactating women.
- Known hypersensitivity to CDK4/6 inhibitors, fulvestrant, or to any of the excipients.
- Radiotherapy within four weeks prior to enrollment (baseline/treatment start) except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment (baseline/treatment start). Patients must have recovered from radiotherapy toxicities prior to enrollment.
- Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.
- Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below: a. short duration (<2 weeks) of systemic corticosteroids is allowed (e.g., chronic obstructive pulmonary disease, anti-emetic); b. low doses of corticosteroids for brain metastasis treatment is allowed.
- Patients with symptomatic visceral disease in need of urgent disease control (e.g., significant dyspnea related to pulmonary lymphangitic carcinomatosis and lung metastases or clinically meaningful symptomatic liver metastasis at the judgement of treating investigator).
- Symptomatic brain metastases.
- Patients with a known history of HIV seropositivity.
- Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin, low-molecular-weight heparin (LMWH) and acetylsalicylic acid or equivalent, as long as the INR is <= 2.0).
- Any severe and/or uncontrolled medical conditions such as: unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction <= 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia.
- Acute and chronic, active infectious disorders.
- Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study treatments (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).
- Inability to swallow oral medications.
- Significant symptomatic deterioration of lung function.
- Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to enrollment.
- History of non-compliance to medical regimens.
- Patients refusing to perform liquid biopsy at study entry and disease progression.
- Patients unwilling to or unable to comply with the protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 18 Oct 2019 | 168 |
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 125 mg hard capsules | Test | HARD CAPSULES | ORAL | 125 | 18 | PRD6503996 |
IBRANCE 125 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 125 | 18 | PRD7907865 |
IBRANCE 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 100 | 18 | PRD7907867 |
IBRANCE 100 mg hard capsules | Test | HARD CAPSULES | ORAL | 100 | 18 | PRD6503927 |
IBRANCE 75 mg hard capsules | Test | HARD CAPSULES | ORAL | 75 | 18 | PRD6503929 |
IBRANCE 75 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 75 | 18 | PRD7907995 |