A Phase II Randomized, Double-Blind Study Comparing Fulvestrant and Palbociclib Versus Fulvestrant and Placebo in HR-Positive Metastatic Breast Cancer
- Trial ID
- 2024-516132-10-00
- Protocol
- GEICAM/2014-12
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of fulvestrant in combination with palbociclib compared to fulvestrant plus placebo, specifically in terms of the rate of **Progression-Free Survival (PFS)** at one year. This is assessed in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer who have previously undergone at least five years of endocrine therapy and have remained disease-free for more than 12 months following its completion, or who have de novo metastatic disease. This objective is clinically relevant as it aims to determine the potential benefit of adding palbociclib to fulvestrant in extending the period during which the disease does not progress, which is a critical factor in the management of metastatic breast cancer.
Secondary objectives include:
- Comparing other efficacy measures between the treatment arms.
- Comparing safety and tolerability between the treatment arms.
- Comparing health-related quality of life between the treatment arms.
Participants
The clinical trial involves a study population of **postmenopausal women** diagnosed with **metastatic breast cancer**. The trial specifically targets individuals who are **hormone receptor-positive** and **HER2-negative**. Participants are required to be at least 18 years of age, with a life expectancy of 12 weeks or more, and must have adequate organ and bone marrow function. The trial does not include male subjects or vulnerable populations. Participants were selected based on their previous treatment history, having received at least five years of endocrine therapy for early disease and remaining disease-free for more than 12 months following its completion, or having de novo metastatic disease. The study also considers lifestyle factors such as the ability to comply with scheduled visits and treatment plans. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy and tolerability of **fulvestrant** in combination with **palbociclib** compared to fulvestrant with placebo in postmenopausal women with hormone receptor-positive, HER2-negative **metastatic breast cancer**. The trial is structured in a parallel-group format and is conducted across multiple centers. The study aims to assess the rate of progression-free survival at one year as the primary endpoint, with secondary endpoints including overall survival, objective response rate, and clinical benefit rate. The trial is expected to last until April 2025, with recruitment having commenced in February 2016.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, life expectancy, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of tumor response and adverse events. The end-of-study visit will conclude the participant's involvement, during which final evaluations will be conducted. The expected duration of participant involvement is up to 480 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent.
The trial involves the administration of fulvestrant as a **solution for injection** and palbociclib as an **oral** medication. Fulvestrant is administered at a maximum daily dose of 500 mg, while palbociclib is administered at a maximum daily dose of 125 mg. The study medication is provided in bottles instead of blisters and boxes, and is labeled as clinical trial medication. Participants are required to comply with scheduled visits, treatment plans, and laboratory tests, and must provide biological samples for biomarker analysis. The trial's methodology ensures rigorous assessment of treatment outcomes, adhering to established clinical and laboratory standards.
Treatment
The clinical trial involves the administration of **Palbociclib**, an experimental medication, which is provided in the form of a hard capsule. The active substance, **Palbociclib**, is of chemical origin. The medication is administered orally with a maximum daily dose of 125 mg and a total maximum dose of 315 mg. The treatment period extends up to 480 days. The medication is supplied in bottles rather than blisters and boxes, and it is labeled as clinical trial medication. Participant compliance is monitored throughout the study to ensure adherence to the dosing schedule.
In addition to the experimental treatment, the study includes the administration of **Fulvestrant**, marketed as Faslodex 250 mg solution for injection. This non-experimental treatment is provided as a standard-of-care therapy. **Fulvestrant** is administered via subcutaneous injection with a maximum daily dose of 500 mg and a total maximum dose of 60,500 mg over the treatment period of 480 days. The medication is labeled as clinical trial medication, and participant compliance is similarly monitored to ensure proper administration and adherence to the dosing schedule.
The trial also includes a placebo group to compare the efficacy of **Fulvestrant** in combination with **Palbociclib** versus **Fulvestrant** plus placebo. The placebo is administered in a manner consistent with the active treatments to maintain the study's double-blind design. Compliance monitoring is conducted to ensure the integrity of the trial results.
Efficacy
The efficacy of the clinical trial will be assessed primarily by evaluating the **Progression-Free Survival (PFS)** rate at 1 year. This will be determined according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, as assessed by the investigator. Secondary efficacy endpoints include the Objective Response Rate (ORR), which encompasses Complete Response (CR) and Partial Response (PR), and the Clinical Benefit Rate (CBR), defined as CR plus PR plus stable disease (SD) lasting at least 24 weeks. Overall Survival (OS) and 1-year and 2-year survival probabilities will also be measured.
Data collection for these endpoints will involve regular assessments using validated criteria and tools. The trial will utilize standard clinical and laboratory tests to monitor safety, with adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Additionally, changes in mean scores and time to deterioration on the EORTC QLQ-C30 Global Health Status/Quality of Life and Physical Function, as well as the EORTC QLQ-BR23 Breast Module, will be evaluated from baseline.
Inclusion and Exclusion Criteria
Inclusion Criteria
- The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
- Availability of a tumor tissue sample, archival (primary tumour) or from the metastatic lesions (preferable) for the central ER, PgR and HER2 testing.
- Histological/cytological confirmation of breast cancer with evidence of metastatic disease (loco-regional or distant), not amenable to resection or radiation therapy with curative intent.
- Documented positive hormone receptor status (>/=1% of tumour cells with oestrogen receptor [ER] and/or progesterone receptor [PgR] expression) based on central testing on the most recent tumour biopsy.
- Documented HER2-negative tumour based on central testing on the most recent tumour biopsy. HER2-negative tumour is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH) defined as a HER2/CEP17 ratio <2 or for single probe assessment a HER2 copy number <4.
- Patients must have received at least 5 years of endocrine therapy in the adjuvant setting as treatment for early disease and remained disease free for more than 12 months following its completion or have de novo metastatic disease.Patients that have been scheduled 5 years with adjuvant endocrine therapy and stopped treatment, by patient's own decision, after completing at least 3 years of treatment, can be also be included as long as they have remained free of disease 3 years after discontinuing the endocrine therapy.
- Patients must have at least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI, plan x-ray or physical examination. Clinical lesions will only be considered measurable when they are superficial and #10mm diameter as assessed using callipers (e.g. skin nodules). Patients with bone-only disease must have a lytic or mixed (lytic + blastic) lesion, which has not been previously irradiated and can be accurately assessed by CT/MRI according to RECIST version 1.1.
- Postmenopausal patient, defined as a woman fulfilling any one of the following criteria (based on the NCCN definition of menopause [National Comprehensive Cancer Network 2008]): Prior bilateral oophorectomy. Age > 60 years. Age ≤ 60 years and with amenorrhea for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle stimulating hormone and estradiol in the postmenopausal range.
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.
- At least 18 years of age.
- Life expectancy ≥ 12 weeks.
- Adequate organ and bone marrow function: ANC ≥ 1,500/mm3 (1.5x109/L); Platelets ≥ 100,000/mm3 (100x109/L); Haemoglobin (Hgb) ≥ 9g/dL (90g/L); Serum creatinine ≤ 1.5xUpper Limit of Normal (ULN) or estimated creatinine clearance ≥ 60ml/min as calculated using the method standard for the institution; Total serum bilirubin ≤ 1.5xULN (<3xULN if Gilbert´s disease); AST and/or ALT ≤ 3xULN (≤5xULN if liver metastases present); Alkaline Phosphatase (AP) ≤ 2.5xULN (≤5xULN if bone or liver metastases present).
- Patients consent to biological sample provision for biomarker exploratory analysis.
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
Exclusion Criteria
- Prior systemic therapy for metastatic disease. Note: patients with a local recurrent disease treated with surgery (R0) and receiving a “second hormonal adjuvant therapy for five years” will be allowed, provided they have remained disease free for more than 12 months following its completion.
- Have “de novo” locally advanced disease.
- Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers, and drugs that are known to prolong the QT interval.
- Presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement, or any degree of brain or leptomeningeal involvement (past or present), or symptomatic pulmonary lymphangitis spread, or any known bone marrow infiltration due to breast cancer. Patients with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not significantly compromised as a result of disease.
- Treatment with a non-approved or experimental drug within 4 weeks before randomization.
- Prior treatment with any CDK4/6 inhibitor or fulvestrant.
- Current or prior malignancy within previous 5 years (other than breast cancer or adequately treated basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix).
- History of: Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor deficiency) or long-term (>6 months) anticoagulant therapy (other than antiplatelet therapy and low dose coumarin derivatives provided that the International Normalised Ratio (INR) is less than 1.6). Hypersensitivity to active or inactive excipients of fulvestrant, palbociclib/placebo or castor oil. Any severe concomitant condition which makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the trial protocol, e.g. uncontrolled cardiac disease or uncontrolled diabetes mellitus.
- QTc interval >480msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
- Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcaemia, hypokalaemia, hypomagnesaemia).
- Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of palbociclib, such as history of GI surgery which may result in intestinal blind loops and patients with clinically significant gastro-paresis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or diarrhoea of CTCAE grade >1.
- Prior hematopoietic stem cell or bone marrow transplantation
- Known human immunodeficiency virus infection.
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Ireland | Not Recruiting | 08 Feb 2016 | 12 |
 Spain | Not Recruiting | 08 Feb 2016 | 177 |
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 |
|---|---|---|---|---|---|---|
Faslodex 250 mg solution for injection. | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 500 | 480 | PRD3545745 |
PALBOCICLIB | Test | — | ORAL | 125 | 480 | SUB177204 |
PALBOCICLIB | Test | — | ORAL | 125 | 480 | SUB177204 |
PALBOCICLIB | Test | — | ORAL | 125 | 480 | SUB177204 |
PALBOCICLIB | Placebo | — | ORAL | 125 | 480 | SUB177204 |
PALBOCICLIB | Placebo | — | ORAL | 125 | 480 | SUB177204 |
PALBOCICLIB | Placebo | — | ORAL | 125 | 480 | SUB177204 |