Evaluation of Chemotherapy Versus Endocrine Therapy as Second-Line Treatment in ER-Positive HER2-Negative Metastatic Breast Cancer Using Fluoroestradiol F-18

Trial ID: 2023-506282-66-00
Protocol: IC 2022-12
Sponsor: Institut Curie

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Diseases & Conditions

Breast cancer metastatic

Objectives

The primary objective of this study is to assess the **efficacy** of chemotherapy (Arm B) versus endocrine therapy (Arm C) as a second-line treatment following CDK4/6 inhibitor therapy in patients with ER-positive HER2-negative metastatic breast cancer. This evaluation is crucial for determining the optimal therapeutic approach for patients who exhibit either unfavorable 18F-FES PET/CT features or high circulating markers, which are indicative of disease progression and may influence treatment outcomes.

Secondary objectives include:

Further assessing the efficacy of chemotherapy (Arm B) versus endocrine therapy (Arm C) in patients with unfavorable 18F-FES PET/CT features and/or high circulating markers.
Evaluating the efficacy of endocrine therapy as a second-line treatment in Arm A, specifically for patients with favorable 18F-FES PET/CT features and low circulating tumor cell (CTC) count.
Assessing the safety and tolerability of the study treatments (chemotherapy or endocrine therapy) and the 18F-FES PET/CT imaging.
Describing changes in Health-Related Quality of Life (HRQOL) among participants.

Participants

The clinical trial involves **female** participants aged 18 years and older, diagnosed with **ER+ HER2- metastatic breast cancer** who have experienced disease progression following first-line therapy with a CDK4/6 inhibitor and an aromatase inhibitor. The study population is exclusively female, with no male participants included, and it is noted that a vulnerable population is selected. Participants are required to have a life expectancy greater than three months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The trial does not provide specific information on the total number of participants. Selection criteria include the availability of a tumor block FFPE and 18F-FDG PET/CT imaging, as well as evaluable disease per RECIST criteria and measurable disease per PERCIST criteria. Participants must have progressed on first-line endocrine therapy after more than six months of treatment and be eligible for second-line endocrine therapy as assessed by the investigator. The sponsor has not provided information on the total number of participants.

Plans and Procedures

The clinical trial is a **randomized**, multicentric, open-label, phase III study designed to evaluate the efficacy of chemotherapy versus endocrine therapy as a second-line treatment in patients with **ER-positive HER2-negative metastatic breast cancer**. The trial aims to assess the combined value of **18F-FES PET/CT** and circulating biomarkers in guiding treatment decisions. The study will involve participants who have progressed on first-line therapy with a CDK4/6 inhibitor and an aromatase inhibitor. The trial is expected to commence recruitment on December 16, 2023, and conclude by June 16, 2028.

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 disease progression. Following randomization, participants will be allocated to either chemotherapy or endocrine therapy arms. Regular follow-up visits will be scheduled to monitor treatment efficacy and safety, with assessments including progression-free survival, overall survival, and adverse events. The primary endpoint is progression-free survival, defined as the time from randomization to disease progression or death. Secondary endpoints include overall survival, objective response rate, and clinical benefit rate at 24 weeks.

The expected duration of participant involvement is contingent upon individual response to treatment and disease progression, with a maximum treatment period of one year. Conditions that may lead to early termination from the study include significant adverse events or withdrawal of consent. The study will utilize **EstroTep 500 MBq/mL, solution injectable**, administered via intravenous injection, with a maximum daily dose of 400 MBq. The trial will adhere to rigorous ethical standards, ensuring informed consent and compliance with protocol-related procedures.

Treatment

The clinical trial involves the administration of **EstroTep 500 MBq/mL**, a **solution for injection** containing the active substance **fluoroestradiol F-18**. This experimental medication is provided in the form of a solution injectable and is administered via **intravenous injection**. The maximum daily dose is set at 400 MBq, with the same limit for the total dose. The treatment period is restricted to a single day. The active substance, fluoroestradiol F-18, is of chemical origin and is utilized to assess the efficacy of chemotherapy versus endocrine therapy in patients with ER-positive HER2-negative metastatic breast cancer.

In addition to the experimental treatment, the study includes standard-of-care therapies as comparator treatments. These therapies consist of chemotherapy and endocrine therapy, which are administered as post-CDK4/6 inhibitor second-line treatments. The choice between chemotherapy and endocrine therapy is determined based on the patient's 18F-FES PET/CT features and circulating biomarker levels. The study aims to evaluate the optimal second-line therapy for patients displaying unfavorable imaging features or high circulating markers.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial does not involve any pediatric formulations, and the experimental medication is not classified as an orphan drug. The pharmaceutical form and administration route are consistent with standard practices for injectable solutions, ensuring the reliability of the treatment delivery.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization to disease progression or death among randomized patients. Secondary endpoints include PFS with available PERCIST tumor evaluation, Overall Survival (OS) among randomized patients in arms B and C, Objective Response Rate (ORR), and Clinical Benefit Rate (CBR) at 24 weeks. These efficacy criteria will also be evaluated in patients allocated to arm A.

Data collection will involve the use of validated criteria such as RECIST for evaluable disease and PERCIST for measurable disease. Additionally, the QLQ-C30 questionnaire will be administered at baseline and after two months of treatment to assess patient-reported outcomes. Adverse events, including Grade 3 or 4 AEs according to NCI CTCAE v5.0, will be recorded, with a focus on their relationship to the study treatments, which include chemotherapy and endocrine therapy. For patients undergoing 18F-FES PET/CT, serious adverse events and any grade AEs will be collected. The trial is designed as a randomized, multicentric, open-label, phase III study, aiming to evaluate the combined value of 18F-FES PET/CT and circulating biomarkers in guiding second-line treatment decisions for ER-positive HER2-negative metastatic breast cancer patients.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Metastatic invasive breast carcinoma of no special type
Females of age ≥18 years.
Life expectancy > 3 months.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
Estrogen Receptor (ER)-positive (≥10%) and HER2-negative (ASCO/CAP guidelines) breast cancer, per local assessment on the most recent breast cancer tissue examined.
Tumor block FFPE (primary tumor or metastasis) available.
Patients whose disease has progressed on first line endocrine therapy with aromatase inhibitor and CDK4/6 inhibitor and who are deemed eligible, per investigator assessment, to a second line endocrine therapy. The progression on first line endocrine therapy with aromatase inhibitor and CDK4/6 inhibitor must have occurred after more than 6 months on treatment.
Patients with available 18F-FDG PET/CT imaging
Evaluable disease per RECIST criteria and measurable disease per PERCIST criteria.
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and any protocol-related procedures including screening evaluations.
Signed informed consent.
Patient affiliated to a social security system.

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Exclusion Criteria

Other breast cancer subtype (e.g. invasive lobular breast carcinoma).
One or more prior line of chemotherapy in the metastatic setting.
Any other antineoplastic therapy given at metastatic disease than the first line therapy with aromatase inhibitor and CDK4/6 inhibitor.
Visceral crisis, per investigator’s assessment.
Liver-only metastases.
Prior exposure to any authorized or experimental agent degrading the estrogen receptor (fulvestrant, oral SERDs, PROTAC, etc).
Pregnancy or lactation period.
In women of childbearing potential or premenopausal women or women with amenorrhea of less than 12 months, without adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization; LHRH agonist cannot be considered as an efficient contraceptive measure), positive urinary or serum pregnancy test 72 hours before 18F-FES PET/CT.
Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease. Patients with a history of CNS metastases or cord compression are eligible if they have been treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable and off anticonvulsants and steroids for at least 4 weeks before treatment start.
History of previous cancer or hematological malignancy within 3 years preceding patient enrollment in the trial. Multiple primary breast cancers (controlateral/ipsilateral cancers/local relapses) are allowed pending all tumors were ER+ HER2-.
Persons deprived of their freedom or under guardianship or incapable of giving consent.