Adjuvant Dynamic Marker-Adjusted Personalized Therapy: Ribociclib Plus Endocrine Therapy Versus Chemotherapy in HR+/HER2- Early Breast Cancer

Trial ID: 2024-515769-32-00
Protocol: WSG-AM08
Sponsor: WSG Westdeutsche Studiengruppe GmbH

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Diseases & Conditions

Breast cancer Hormone receptor positive breast cancer Breast cancer female Hormone receptor positive HER2 negative breast cancer

Objectives

The primary objective of this study is to demonstrate the **superiority** in invasive disease-free survival (iDFS) of ribociclib combined with endocrine therapy (ET) compared to standard-of-care chemotherapy in patients with intermediate-risk, HR+/HER2- early breast cancer. Additionally, the study aims to achieve a survival rate greater than 92% in 5-year distant disease-free survival (dDFS) in the ribociclib plus ET group. This is clinically relevant as it may offer a more effective treatment option with potentially fewer side effects compared to traditional chemotherapy, improving patient outcomes in this specific breast cancer subtype.

Secondary objectives include: - Evaluating overall survival (OS) and dDFS in both treatment arms. - Assessing differences in OS and dDFS. - Conducting subgroup and multivariable survival analyses based on key clinical, genomic, and endocrine-response parameters. - Measuring quality of life (QoL) and its correlation to treatment-related symptoms using EQ-VAS and a triggered symptom questionnaire. - Analyzing treatment adherence. - Comparing Ki-67 values measured by local versus central pathologists in all tissue samples. - Comparing pathological complete response (pCR) by treatment arm. - Comparing clinical response rate by treatment arm. - Comparing the prevalence of breast conservation therapy versus mastectomy by treatment arm.

Participants

The clinical trial involves a study population exclusively comprising **female** participants aged **18 years and older**. The trial focuses on individuals diagnosed with **HR+/HER2- early breast cancer**. Participants are required to have a histologically confirmed diagnosis of primary estrogen-receptor positive and/or progesterone-receptor positive early breast cancer, with HER2-negative status confirmed by local laboratory tests. The trial does not include male participants, and the sponsor has not provided the total number of participants. The selection criteria emphasize the absence of distant metastasis and adequate bone marrow and organ function. Participants must be able to swallow ribociclib tablets and comply with study procedures. The trial population includes both pre-menopausal and post-menopausal women, with specific criteria for each group regarding menopausal status and pregnancy testing. The study does not provide specific information on lifestyle considerations such as diet or physical activity. The sponsor has not disclosed the total number of participants involved in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **ribociclib** in combination with endocrine therapy compared to standard chemotherapy in patients with intermediate-risk, hormone receptor-positive (HR+)/HER2-negative early breast cancer. This is a Phase III, randomized, double-blind, controlled trial. The primary objective is to demonstrate superiority in invasive disease-free survival (iDFS) and achieve a survival rate greater than 92% in 5-year distant disease-free survival (dDFS) in the ribociclib plus endocrine therapy group. The trial is expected to conclude by July 2028, with recruitment having commenced in February 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate bone marrow and organ function, ECOG performance status, and menopausal status. Following randomization, participants will attend regular follow-up visits to monitor treatment adherence, assess clinical response, and evaluate quality of life. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.

The expected duration of participant involvement is up to 24 months, corresponding to the maximum treatment period with ribociclib. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will utilize **Kisqali 200 mg film-coated tablets** administered orally, with a maximum daily dose of 600 mg. The study aims to provide valuable insights into the potential benefits of ribociclib in improving outcomes for patients with this specific subtype of breast cancer.

Treatment

The clinical trial involves the administration of **Kisqali** 200 mg film-coated tablets, which contain the active substance **ribociclib**. Ribociclib is a chemical compound classified under the ATC code L01EF02. The pharmaceutical form of the medication is a film-coated tablet, designed for **oral use**. The maximum daily dose of ribociclib is 600 mg, with a total maximum dose of 327,600 mg over the course of the treatment. The treatment period is set to a maximum of 24 months. The tablets are manufactured by Novartis Europharm Limited and are labeled specifically for the study. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.

In addition to the experimental treatment with ribociclib, the study includes a comparator treatment, which is the standard-of-care chemotherapy. This non-experimental treatment serves as a control to evaluate the efficacy of ribociclib in combination with endocrine therapy. The trial aims to demonstrate the superiority of ribociclib plus endocrine therapy over standard chemotherapy in terms of invasive disease-free survival and distant disease-free survival rates in patients with intermediate-risk, HR+/HER2- early breast cancer. The study protocol ensures that all participants receive appropriate monitoring and follow-up to assess treatment outcomes and safety.

Efficacy

Efficacy in the clinical trial will be assessed using primary and secondary endpoints. The primary endpoints include **invasive disease-free survival (iDFS)** and **distant disease-free survival (dDFS)**. These parameters will be used to evaluate the superiority of ribociclib combined with endocrine therapy (ET) compared to standard-of-care chemotherapy in patients with intermediate-risk, hormone receptor-positive (HR+)/HER2-negative early breast cancer.

Secondary endpoints will encompass overall survival (OS), quality of life (QoL), treatment adherence measured by drug intake, and local and central Ki-67 values in all tissue samples. Additional secondary endpoints include pathological response rate, defined as ypT0/is/ypN0, and further definitions such as ypT0/ypN0, ypT0/is/any ypN, and near pCR (ypT1a/any ypN). Clinical response rate will be assessed through palpation, ultrasound, and other methods, alongside the rate of breast-conservation therapy.

The trial aims to demonstrate a survival rate greater than 92% in 5-year dDFS in the ribociclib plus ET group. The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, which is estimated to conclude by July 31, 2028. The trial is categorized as a Phase III clinical trial, indicating its advanced stage in the clinical research process.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent prior to any screening procedures.
Female.
≥ 18 years of age.
4a. EITHER: (Post)menopausal status at the time of initiation of (neo)adjuvant study medication: patient underwent bilateral oophorectomy, or age ≥ 60, or age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and/or FSH and oestradiol in the postmenopausal range per local normal range. 4b. OR: Pre-menopausal patients: confirmed negative serum or urine pregnancy test (β-hCG) before starting study treatment, or patient has had a hysterectomy.
Histologically confirmed diagnosis of primary oestrogen-receptor positive and/or progesterone-receptor positive (≥ 1%) early breast cancer by local laboratory.
Patient has HER2-negative breast cancer defined as a negative in-situ hybridization test or an IHC status of 0, 1+, or 2+, if IHC is 2+, a negative in-situ hybridization (FISH, CISH, or SISH) test is required (based on the most recently analysed tissue sample and all tested by a local laboratory).
Local therapy of breast cancer (if adjuvant treatment or planned if neoadjuvant treatment) according to current guidelines. Note: This may include radiotherapy of breast cancer. Radiotherapy may be performed in parallel or sequentially to either ribociclib or standard of care treatment, as per investigator´s decision.
No evidence of distant metastasis (confirmed prior to randomization by CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT, respectively).
Patient has available tumour tissue from primary diagnostic biopsy.
Patient is classified as intermediate risk according to the ADAPT intermediate to high-risk definition (i) (as follows), or (only in case of missing Oncotype DX® data), according to the clinical intermediate-risk definition (ii) (as follows). (For detailed information see study protocol)
No contraindication for (neo)-adjuvant ET and/or chemotherapy
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
Patient has adequate bone marrow and organ function as defined by the following laboratory values: absolute neutrophil count ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, haemoglobin ≥ 9.0 g/dL, estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula, INR ≤ 1.5, serum creatinine < 1.5 mg/dL, total bilirubin < ULN, except for patients with Gilbert’s Syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN, aspartate transaminase (AST) < 2.5 × ULN, alanine transaminase (ALT) < 2.5 × ULN.
12-lead-ECG with: QTcF interval at screening < 450 msec (using Fridericia’s correction), mean resting heart rate 50-90 bpm (determined from the ECG).
Ability to swallow ribociclib tablets or to administer other study medication, respectively.
Ability to communicate with the investigator and comply with study procedures.
Willing to remain during therapy at the clinical site, as required by the protocol.

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Exclusion Criteria

Patient with distant metastases of breast cancer beyond regional lymph nodes.
Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1.
Patient has a concurrent malignancy, or malignancy within 5 years prior to randomization, or known history of invasive breast cancer.
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small-bowel resection).
Patient has a known history of HIV infection. Screening for HIV- infection and testing for HIV is highly recommended according to current valid (local) clinical guidelines, but neither part of the interventional study procedures, nor required for enrolment.
Patient has known active hepatitis-B-virus (HBV) or hepatitis-C- virus (HCV) infection. Screening for HBV or HBC-infection and testing for hepatitis-B or -C is highly recommended according to current valid (local) clinical guidelines, but neither part of the interventional study procedures, nor required for enrollment.
Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator´s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study, or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial, or viral infections, etc.).
Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: history of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry, documented cardiomyopathy, left ventricular ejection fraction (LVEF) < 50 % as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO), long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome, or any of the following: risk factors for Torsades de Pointe (TdP, polymorphic ventricular tachycardia in patients with long QT syndrome) including uncorrected hypokalaemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia, concomitant medications with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug), inability to determine the QTcF interval, clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left-bundle branch block, high-grade AV block (e.g., bi-fascicular block, Mobitz type II, and 3rd-degree AV block), systolic blood pressure (SBP) > 160 or < 90 mmHg.
Patient has received prior (neo)-adjuvant treatment with chemotherapy, ET, or any CDK4/6 inhibitor for breast cancer.
Patient has received tamoxifen, raloxifene, or aromatase inhibitors (AIs) for reduction in risk (“chemoprevention”) of breast cancer and/or treatment for osteoporosis within last 2 years prior to screening.
Patient has received prior neoadjuvant/adjuvant treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin.
Patient with a known hypersensitivity to any of the excipients of ribociclib, ET, or standard-of-care chemotherapy.
Patient with inflammatory breast cancer at screening.
Patient is concurrently using other anti-cancer therapy.
Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
Patient is currently receiving warfarin or other coumarin-derived anti-coagulant for treatment, prophylaxis, or otherwise.
Patient is currently receiving any of the following substances, which cannot be discontinued 7 days prior to Cycle 1 Day 1: concomitant medications, herbal supplements, fruits (e.g., grapefruit, pomegranates, pomelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5, medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.
Participation in another investigational study in which the patient´s IMP-treatment is not yet completed and up to 30 days after ending of IMP-treatment in this respective investigational study
Not able to understand and to comply with study instructions and requirements.
Pregnant or nursing (lactating) woman.
Woman of child-bearing potential defined as woman physiologically capable of becoming pregnant, unless she is using highly effective methods of contraception during the study treatment and for 21 days after stopping the treatment: total abstinence (when this is in line with the preferred and usual lifestyle of the patient). female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. male partner sterilization (at least 6 months prior to study screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient. placement of an intrauterine device (IUD).
Use of oral (oestrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.