Comparative Evaluation of Giredestrant and Triptorelin Versus Anastrozole and Triptorelin in Premenopausal ER-Positive/HER2-Negative Early Breast Cancer
- Trial ID
- 2022-503013-32-00
- Protocol
- 67-22 PREcoopERA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **anti-proliferative activity** of a 4-week treatment with giredestrant plus triptorelin compared to anastrozole plus triptorelin in premenopausal patients with ER-positive/HER2-negative operable invasive breast cancer. Additionally, the study aims to determine if giredestrant without triptorelin provides similar (non-inferior) anti-proliferative activity compared to giredestrant plus triptorelin. This is clinically relevant as it may offer insights into optimizing hormone therapy regimens for this patient population, potentially improving treatment outcomes and reducing side effects associated with triptorelin.
Secondary objectives include:
- Assessing if 4 weeks of giredestrant without triptorelin provides greater anti-proliferative activity than anastrozole plus triptorelin among the same patient group.
- Evaluating the safety and tolerability of giredestrant with or without triptorelin over a 4-week period in premenopausal patients with ER-positive/HER2-negative operable invasive breast cancer.
Participants
The clinical trial involves a total of **45 participants** who are premenopausal women aged 18 years and older. The study population is specifically selected to include individuals with **ER-positive/HER2-negative early breast cancer**. Participants are required to have a histologically confirmed, operable invasive breast carcinoma and must be eligible for upfront breast conservative surgery or mastectomy, with tumor sizes of at least 1.0 cm. The trial excludes individuals with distant metastatic disease. All participants must have a documented estrogen receptor-positive tumor and a human epidermal growth factor receptor-2 negative tumor, as per local assessments. The trial population is characterized by a good general health status, as indicated by an Eastern Cooperative Oncology Group Performance Status of 0-1, and normal hematologic, renal, and liver function. Lifestyle considerations include the requirement for participants to have been menstruating regularly without hormonal treatments in the six months prior to screening. The trial does not include male subjects, and the population is considered vulnerable. Participants must agree to the submission of tumor and blood samples for central pathology review and translational studies. The sponsor has not provided additional information regarding specific lifestyle habits such as diet or physical activity.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **giredestrant** in combination with **triptorelin** compared to **anastrozole** plus triptorelin in premenopausal patients with ER-positive/HER2-negative early breast cancer. This is a randomized, double-blind, controlled trial with an estimated duration from December 2023 to December 2025. The trial involves a sequence of study visits, beginning with a screening visit to confirm eligibility based on criteria such as premenopausal status, tumor characteristics, and overall health. Participants will be randomly assigned to one of the treatment arms and will receive the assigned treatment for a period of four weeks.
Study visits will include baseline assessments, treatment administration, and follow-up evaluations to monitor the primary endpoint, which is the change in Ki-67 levels between pre-treatment and post-treatment tumor biopsies. Secondary endpoints include complete cell cycle arrest and the assessment of adverse events according to CTCAE v5.0. The end-of-study visit will involve a comprehensive evaluation of the treatment's impact and any adverse effects experienced by the participants.
Participants are expected to be involved in the study for approximately 32 days, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. The trial aims to provide insights into the anti-proliferative activity of the treatments, contributing to the understanding of effective therapeutic strategies for this patient population.
Treatment
The clinical trial involves the administration of **Arimidex 1 mg Filmtabletten**, which contains the active substance **anastrozole**. This medication is provided in the form of a **film-coated tablet** and is administered orally. The dosage is set at 1 mg per day, with a maximum total dose of 32 mg over a treatment period of 32 days. Anastrozole functions as an aromatase inhibitor, which is commonly used in the treatment of estrogen receptor-positive breast cancer. Participant compliance with the dosing schedule will be monitored throughout the trial.
Another treatment used in the trial is **Pamorelin® LA 3.75 mg**, which contains the active substance **triptorelin**. This medication is supplied as a **prolonged-release suspension for injection** and is administered intramuscularly. The dosage is 3.75 mg, with a maximum total dose of 7.5 mg over the same 32-day treatment period. Triptorelin acts as a gonadotropin-releasing hormone (GnRH) agonist, which is utilized to suppress ovarian function in premenopausal women with hormone-sensitive breast cancer. The administration schedule and participant adherence will be closely monitored.
The experimental medication **RO7197597**, also known as **giredestrant**, is provided in the form of a **hard capsule**. This selective estrogen receptor degrader (SERD) is administered orally at a dosage of 30 mg per day, with a maximum total dose of 960 mg over the 32-day treatment period. Giredestrant is being investigated for its potential to provide anti-proliferative activity in estrogen receptor-positive breast cancer. Compliance with the dosing regimen will be assessed to ensure accurate data collection.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the change in **Ki-67** levels, a marker of cell proliferation, measured by immunohistochemistry (IHC) in a central laboratory. The primary endpoint is the change in the **Ki-67-labeling index**, which is the percentage of immunostaining cells, between a pre-treatment tumor biopsy and a post-treatment tumor re-biopsy. This change will be analyzed on a natural logarithmic scale to determine the anti-proliferative activity of the treatments being studied.
Secondary endpoints include the assessment of complete cell cycle arrest (CCCA), defined as **Ki-67** ≤2.7% on post-treatment tumor re-biopsy, evaluated through visual image analysis. Additionally, adverse events will be monitored and categorized according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. These efficacy parameters will be collected and analyzed at specified timepoints, ensuring a comprehensive evaluation of the treatment's impact on premenopausal patients with ER-positive/HER2-negative early breast cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Premenopausal women age ≥18 years, premenopausal status defined as: o Estradiol (E2) in the premenopausal range (according to institution parameters) or o Patient has been menstruating regularly during the 6 months prior to screening and has not used any form of hormonal contraception or any other hormonal treatments during this time. • Histologically confirmed, operable invasive breast carcinoma. • Eligible for upfront breast conservative surgery or upfront mastectomy: stage I, stage II or operable stage III (excludes T4) o Tumor size must be ≥1.0 cm o Multicentric and multifocal tumors and bilateral breast cancers are allowed but investigators must ensure the same tumor foci is biopsied pre-treatment and post-treatment (e.g., via clipping of the biopsied tumor foci). o Patients with distant metastatic disease are not eligible. • Documented estrogen receptor (ER)-positive tumor in accordance to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, assessed locally and defined as ≥1% of tumor cells stained positive. • Documented human epidermal growth factor receptor-2 (HER2)-negative tumor in accordance to 2018 ASCO/CAP guidelines, as determined per local assessment. • Ki-67 ≥10% in diagnostic biopsy as determined per local assessment. • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. • Resting heart rate ≥40 bpm. • Normal hematologic, renal and liver function • Negative serum or urine beta HCG pregnancy test within 5 weeks prior to randomization. • Pregnancy test will be repeated on day 1, before the first dose of WOO treatment. Women of childbearing potential must use highly effective contraceptive methods during the treatment period and for 10 days after the final dose. • Written Informed Consent (IC) must be signed and dated by the patient and the Investigator prior to randomization. • The patient agrees to the submission of tumor (diagnostic core biopsy and re-biopsy) and blood samples for Central Pathology Review (CPR) and for translational studies as part of this protocol. Note: CPR on the primary tumor is mandatory for this trial, but patients will be evaluated for eligibility according to tumor characteristics as determined by the local pathologist. Both the diagnostic breast core biopsy specimen and the specimen from the re-biopsy or from the breast surgery after the WOO treatment is completed must be submitted for CPR, which will be done by the IBCSG Central Pathology Office in Milan, Italy.
Exclusion Criteria
- Stage IV (metastatic) breast cancer. • Inflammatory breast cancer (cT4d). • Previous systemic or local treatment for the primary breast cancer currently under investigation. • Received any GnRH/LHRH analog within 12 months prior to randomization. • Major surgery within 4 weeks prior to randomization. • Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including hepatitis. • 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. • History of documented hemorrhagic diathesis, coagulopathy, or thromboembolism. • Active cardiac disease or history of cardiac dysfunction. • History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias. • Current treatment with medications that are well known to prolong the QT interval. • Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment. • Known issues with swallowing oral medication. • Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery including gastric resection. • Serious infection requiring oral or IV antibiotics. • Any active tumor of non-breast-cancer histology. • Women who are pregnant or in the period of lactating. • Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Dec 2023 | 10 |
 Germany | Not Recruiting | 01 Dec 2023 | 40 |
 Hungary | Not Recruiting | 01 Dec 2023 | 15 |
 Ireland | Not Recruiting | 01 Dec 2023 | 15 |
 Italy | Not Recruiting | 01 Dec 2023 | 45 |
 Spain | Not Recruiting | 01 Dec 2023 | 45 |
 Sweden | Not Recruiting | 01 Dec 2023 | 5 |
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 |
|---|---|---|---|---|---|---|
Pamorelin® LA 3,75 mg Pulver und Lösungsmittel zur Herstellung einer Depot-Injektionssuspension | Test | PULVER UND LÖSUNGSMITTEL ZUR HERSTELLUNG EINER DEPOT-INJEKTIONSSUSPENSION | INTRAMUSCULAR | 3.75 | 32 | PRD391078 |
RO7197597 | Test | CAPSULE, HARD | ORAL USE | 30 | 32 | PRD9491575 |
ANASTROZOLE ACCORD 1 mg, comprimé pelliculé | Test | COMPRIMÉ PELLICULÉ | ORAL USE | 1 | 32 | PRD385954 |