Phase III Randomized Study Comparing Chemotherapy Versus Endocrine Therapy with Abemaciclib in ER+ HER2- Breast Cancer with Visceral Metastases
- Trial ID
- 2024-513005-31-00
- Protocol
- UC-0140/1901
- Sponsor
- Unicancer
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of a combination of standard Endocrine Therapy with Abemaciclib versus standard Chemotherapy in terms of **progression-free survival (PFS)** in patients with visceral metastases of Estrogen Receptor positive (ER+), Human Epidermal Growth Factor Receptor-2 negative (HER2-) breast cancer, characterized by a high tumor burden. This comparison is clinically relevant as it aims to determine the most effective initial metastatic treatment strategy for this patient population, potentially improving patient outcomes and guiding treatment decisions.
Secondary objectives include:
- Comparing the two study arms in terms of PFS rate at week 24.
- Evaluating Health-Related Quality of Life (HRQOL) and Patient Reported Outcomes (PRO).
- Assessing Objective Response Rate (ORR) and Duration of Response (DoR).
- Comparing Progression-Free Survival 1 (PFS 1) and Progression-Free Survival 2 (PFS 2).
- Analyzing PFS1 and PFS2 in prespecified subgroups defined by stratification factors.
- Comparing Overall Survival (OS) between the two study arms.
- Evaluating the safety profile of the treatments.
- Describing maintenance regimens in patients randomized to the Chemotherapy arm after standard treatment and in the absence of disease progression.
- Studying the predictive and prognostic value of circulating tumor cell count assessed at baseline.
Participants
The clinical trial involves a study population of **female** patients aged 18 years and older, diagnosed with untreated metastatic **Estrogen Receptor positive (ER+)**, **Human Epidermal Growth Factor Receptor-2 negative (HER2-)** breast cancer with visceral involvement. The sponsor has not provided the total number of participants. The trial population was selected based on specific inclusion criteria, including histologically confirmed adenocarcinoma of the breast, metastatic disease with high tumor burden, and adequate renal, hepatic, and hematopoietic functions. Participants are required to have a performance status of ECOG 0-2 and must be considered candidates for first-line chemotherapy in a metastatic setting. Non-menopausal women will receive LH-RH agonists as part of the treatment protocol. Lifestyle considerations such as diet and physical activity are not specified. The trial does not include male subjects and involves a vulnerable population. Participants must have health insurance coverage and demonstrate willingness and ability to comply with the study's requirements.
Plans and Procedures
The clinical trial is designed as an open-label, randomized, multicenter, phase III study aimed at comparing the efficacy of standard **endocrine therapy** combined with **abemaciclib** versus standard chemotherapy in patients with untreated metastatic **estrogen receptor positive (ER+)**, **human epidermal growth factor receptor-2 negative (HER2-)** breast cancer with visceral involvement. The primary objective is to assess progression-free survival (PFS) in these patients. The trial is expected to run from June 2020 to December 2028, with participants involved for a maximum treatment period of 21 to 29 days, depending on the specific treatment regimen.
Participants will be randomly assigned to receive either the combination of endocrine therapy with abemaciclib or standard chemotherapy, which may include agents such as **paclitaxel**, **capecitabine**, **anastrozole**, **letrozole**, or **fulvestrant**. The trial will follow a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as ER and HER2 status, adequate organ function, and performance status. Following randomization, participants will undergo regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will include assessments such as radiological evaluations and quality of life questionnaires at specified intervals.
The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression, unacceptable toxicity, or withdrawal of consent. Participants may be removed from the study early if they experience significant adverse effects, fail to comply with study procedures, or if the investigator deems it in their best interest. The trial will utilize progression-free survival as the primary endpoint, with secondary endpoints including overall survival, quality of life assessments, and radiological response rates. Safety evaluations will be conducted according to the CTCAE V5.0 criteria.
Treatment
The clinical trial involves the administration of several **experimental medications** and standard treatments. **Paclitaxel** is utilized as a concentrate for solution for infusion, administered via **intravenous use**. The maximum daily dose is 80 mg/m², with a total dose not exceeding 240 mg/m² over a 21-day treatment period. This medication is a chemical substance and is not formulated for pediatric use.
**Capecitabine** is provided in the form of a film-coated tablet for **oral use**. The maximum daily dose is 2500 mg/m², with a total dose of up to 35000 mg/m² over a 21-day period. This chemical substance is also not intended for pediatric patients.
**Anastrozole** is administered as a film-coated tablet for **oral use**. The maximum daily dose is 1 mg, with a total dose of 21 mg over the 21-day treatment period. This medication is a chemical substance and is not designed for pediatric use.
**Letrozole** is available as a film-coated tablet for **oral use**. The maximum daily dose is 2.5 mg, with a total dose of 52.5 mg over a 21-day period. This chemical substance is not suitable for pediatric patients.
**Abemaciclib**, marketed as Verzenios 50 mg film-coated tablets, is administered for **oral use**. The maximum daily dose is 300 mg, with a total dose of 6300 mg over a 21-day treatment period. This chemical substance is not formulated for pediatric use, and changes to the labeling have been made for this investigational medicinal product.
**Fulvestrant** is provided as a solution for injection in a pre-filled syringe for **intramuscular use**. The maximum daily dose is 500 mg, with a total dose of 1500 mg over a 29-day period. This chemical substance is not intended for pediatric use.
Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the treatment regimen. The trial aims to compare the efficacy of standard endocrine therapy combined with Abemaciclib versus standard chemotherapy in patients with visceral metastases of ER+ HER2- breast cancer, focusing on progression-free survival as the primary endpoint.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **progression-free survival (PFS)**. PFS will be measured from the date of randomization until the date of the first documented progression, as defined by RECIST v1.1, or death from any cause. Patients without an event at the time of analysis will be censored at the date of the last available tumor assessment or last follow-up visit, whichever occurs first. If patients switch to another therapy, they will be censored at the time of the treatment change.
Secondary endpoints include several measures: PFS within 24 weeks, overall survival (OS), and radiological response rates according to RECIST v1.1. The overall response rate (ORR) will be defined as the proportion of patients achieving a complete response (CR) or partial response (PR) at 24 weeks. The duration of response (DoR) will be calculated from the time of tumor response until objective progression. PFS1 and PFS2 will be evaluated, with PFS1 defined as the interval between randomization and progression or death, and PFS2 as the time from randomization to second progression or death. Additionally, quality of life will be assessed using the EORTC QLQ-C30 and QLQ-BR23 questionnaires, administered at baseline and every 6 weeks for 24 weeks. The G8 questionnaire will be used for patients older than 70 at baseline.
Safety will be evaluated according to CTCAE V5.0. Serial circulating tumor cell (CTC) counts will be performed using the CellSearch® system on blood samples to assess the predictive and prognostic value of CTC status on overall response rate, PFS within 24 weeks, PFS1, and PFS2. These assessments will be conducted throughout the treatment period in both arms of the study.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient must have signed a written informed consent form prior to any study specific procedures
- Female age ≥ 18 years
- Performance status, ECOG 0-2
- Histologically confirmed adenocarcinoma of the breast
- Metastatic breast cancer, with liver and/or lung and/or pleural and/or peritoneal metastases with high tumor burden (according to RECIST v1.1) defined as either visceral involvement of one site with more than 3 lesions
- Metastatic breast cancer, with liver and/or lung and/or pleural and/or peritoneal metastases with high tumor burden (according to RECIST v1.1) defined as either visceral involvement of at least 2 sites
- Metastatic breast cancer, with liver and/or lung and/or pleural and/or peritoneal metastases with high tumor burden (according to RECIST v1.1) defined as either symptomatic ascites or pleural effusion, defined as the need for weekly drainage with visceral measurable metastases
- Metastatic breast cancer, with liver and/or lung and/or pleural and/or peritoneal metastases with high tumor burden (according to RECIST v1.1) defined as either visceral involvement and LDH > N
- Patient considered candidate for a first line chemotherapy in metastatic setting by their physician (either capecitabine or paclitaxel) and who may receive first-line endocrine therapy combined with abemaciclib according to the marketed authorization
- ER-positive by IHC (>10%) on primary or metastatic disease
- HER2-negative by IHC (score 0 or 1+) and/or Fish/Cish negative
- Non-menopausal women will receive LH-RH agonists before starting the endocrine therapy and every 28 days thereafter. It is recommended that LHRH agonist therapy be started approximately 28 days before the start of hormone therapy
- Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria: Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 or ≥ 1.5 G/L
- Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria: Platelets ≥ 100,000/mm3 or ≥ 100 G/L
- Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria: Hemoglobin ≥ 8 g/dL (patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion)
- Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria: Serum Aspartate Transaminase (AST) and serum Alanine Aminotransferase Transaminase (ALT) ≤ 3 x upper limit of normal (ULN) (< 5 ULN if liver metastasis)
- Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria: Total serum bilirubin ≤ 1.5 x ULN (patients with Gilbert’s syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted)
- Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria: Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance > 60 mL/min as calculated using the standard method for the institution
- Women of childbearing potential agreeing to use highly effective contraception during treatment and for 3 weeks following the last dose of abemaciclib or for 6 months following the last dose of capecitabine or paclitaxel or for 2 years following the last dose of fulvestrant
- Women of childbearing potential must have a negative serum pregnancy test within 7 days and/or urine pregnancy test 48 hours prior to the administration of any study treatment
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures
- Health insurance coverage
Exclusion Criteria
- Bone lesion only or non-measurable lesion (RECIST V1.1)
- Patients with all target lesions in a previously irradiated region, except if clear progression has been observed prior to study in at least one of them
- Spinal cord compression and/or symptomatic or progressive brain metastases (Brain metastasis are not acceptable unless asymptomatic or treated and stable off steroids for at least 30 days prior to start of study drug)
- Patient with visceral crisis as defined in the 4th ESO–ESMO International Consensus Guidelines (severe organ dysfunction as assessed by signs and symptoms, laboratory studies and rapid progression of disease)
- Patient has received one line of chemotherapy for metastatic disease
- Patient has received endocrine therapy for metastatic disease
- Inability to swallow orally administered medication
- Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and randomization
- Major problem with intestinal absorption
- Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix or the breast, and adequately treated basal cell or squamous cell carcinoma of the skin
- Patient has active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment
- Patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest
- Patient has any serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30 mL/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea)
- Any drug or plant derivative that may interact with abemaciclib
- Episode of pulmonary thromboembolism (PTE) in the last six months. Patients with deep vein thrombosis previously treated with a low-molecular-weight heparin for more than two months prior enrolment in the study will be eligible
- Patients with previously documented total/partial dihydropyrimidine dehydrogenase (DPD) deficiency or with DPD deficiency identified at baseline visit (plasma uracil concentration ≥ 16 ng/mL). These patients will be not eligible for chemotherapy by capecitabine
- Pregnant or breast feeding women.
- Patients enrolled in another therapeutic study within 30 days prior inclusion
- Individuals deprived of liberty or placed under the authority of a tutor
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 11 Jun 2020 | 180 |
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 |
|---|---|---|---|---|---|---|
LETROZOLE | Test | — | ORAL USE | 2.5 | 21 | SUB08444MIG |
ANASTROZOLE | Test | — | ORAL USE | 1 | 21 | SUB05502MIG |
CAPECITABINE | Comparator | — | ORAL USE | 2500 | 21 | SUB12474MIG |
PACLITAXEL | Comparator | — | INTRAVENOUS USE | 80 | 21 | SUB09583MIG |
CAPECITABINE | Comparator | — | ORAL USE | 2500 | 21 | SUB12474MIG |
Verzenios 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 300 | 21 | PRD6701102 |
FULVESTRANT | Test | — | INTRAMUSCULAR USE | 500 | 29 | SUB13933MIG |