Phase III Randomized Controlled Trial of Abemaciclib Plus Endocrine Therapy Versus Endocrine Therapy in HR+/HER2- Early Breast Cancer with Intermediate to High Risk

Trial ID: 2023-509242-35-00
Protocol: WSG-AM11
Sponsor: WSG Westdeutsche Studiengruppe GmbH

Trial statistics

science

test molecule

location_city

research sites

public

countries

medical_information

diseases

person_search

investigators

handshake

vendors

Diseases & Conditions

Breast cancer Hormone receptor positive breast cancer Breast cancer female Human epidermal growth factor receptor negative

Objectives

The primary objective of this study is to demonstrate the superiority of **abemaciclib** combined with standard adjuvant endocrine therapy (ET) over standard ET alone in improving invasive disease-free survival (iDFS) in patients with HR+/HER2- early breast cancer. This is clinically relevant as improving iDFS can potentially lead to better long-term outcomes and reduce the risk of cancer recurrence in this patient population.

Secondary objectives include evaluating:

Overall survival (OS) and distant disease-free survival (dDFS) in both treatment arms.
Differences in OS and dDFS between the treatment groups.
Subgroup and multivariable survival analyses to identify specific patient characteristics that may influence outcomes.
The occurrence of central nervous system (CNS) metastases, which is critical for understanding the spread of cancer to the brain.
Patient-reported outcomes and quality of life using standardized questionnaires (EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L), providing insights into the impact of treatment on daily living.
Translational research to explore potential biomarkers and mechanisms of action that could inform future therapeutic strategies.

Participants

The clinical trial involves a study population of **female** participants aged 18 years and older, diagnosed with **HR+/HER2- early breast cancer**. The trial does not include male participants. The sponsor has not provided the total number of participants. Participants were selected based on specific criteria, including the absence of distant metastasis, adequate bone marrow and organ function, and the ability to comply with study procedures. All participants must have completed primary therapy for breast cancer according to current guidelines. The trial population includes both pre-menopausal and post-menopausal women, with considerations for menopausal status and reproductive health. Participants are required to have a histologically confirmed diagnosis of primary estrogen-receptor positive and/or progesterone-receptor positive early breast cancer, and HER2-negative status. The trial also considers lifestyle factors such as the ability to swallow medication and willingness to receive therapy as per protocol. The study population is characterized by a vulnerable group, as it includes individuals with a significant medical condition. The sponsor has not provided information on the total number of participants.

Plans and Procedures

The clinical trial is designed as a **randomized**, controlled, open-label, phase III study to evaluate the efficacy of **abemaciclib** combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in patients with HR+/HER2- early breast cancer. The primary objective is to demonstrate superiority in invasive disease-free survival (iDFS) of the combination therapy compared to standard therapy. The trial is expected to run from August 2020 to March 2028, with a maximum treatment period of 24 months for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as no clinical evidence of distant metastasis, adequate bone marrow and organ function, and a histologically confirmed diagnosis of primary estrogen-receptor positive and/or progesterone-receptor positive early breast cancer. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, as well as to assess primary and secondary endpoints, including overall survival (OS), distant disease-free survival (dDFS), and the occurrence of CNS metastases. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.

Participant involvement is expected to last up to 24 months, with conditions for early termination including the occurrence of unacceptable adverse events, withdrawal of consent, or any other reason deemed necessary by the investigator. The study will adhere to rigorous ethical standards, ensuring that all participants provide written informed consent prior to any study procedures. The trial will utilize **oral administration** of abemaciclib, with a maximum daily dose of 300 mg, and will be conducted in compliance with applicable regulatory requirements and guidelines.

Treatment

The clinical trial involves the use of **abemaciclib**, an experimental medication, which is a **CDK4/6 inhibitor**. Abemaciclib is administered in the form of a **film-coated tablet**. The route of administration is **oral use**. The maximum daily dose of abemaciclib is 300 mg, with a total maximum dose amounting to 219 grams over the course of the treatment. The treatment period is set for a maximum of 24 months. The medication is specifically labeled for the study, and it is not formulated for pediatric use. The active substance, abemaciclib, is of chemical origin.

In addition to the experimental treatment, the study includes a comparator treatment, which is the standard adjuvant endocrine therapy (ET). This therapy serves as the control arm in the trial, allowing for a comparison of the efficacy of abemaciclib combined with standard ET versus standard ET alone. The trial aims to demonstrate the superiority of the combination therapy in terms of invasive disease-free survival in patients with intermediate to high-risk, HR+/HER2- early breast cancer.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **invasive disease-free survival (iDFS)** since randomization. Secondary endpoints include iDFS since primary diagnosis, overall survival (OS) and distant disease-free survival (dDFS) since randomization and primary diagnosis, as well as the occurrence of central nervous system (CNS) metastases since both randomization and primary diagnosis. Additionally, subgroup and multivariable survival analyses will be conducted, defined by key clinical, genomic, and endocrine response parameters. Patient-reported outcomes and quality of life will be evaluated using the EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D-5L instruments. The efficacy of therapy will also be analyzed according to distinct clinical and biological prognostic subgroups, measured by genomic signatures and other markers.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Written informed consent prior to any study procedures (outcomes of standard-of-care procedures performed before signing of informed consent by the patient but within the allowed screening period can be used for patient screening).
Female.
≥ 18 years of age.
a) EITHER: (Post)menopausal status at the time of initiation of 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, or ovarian suppression) and/or FSH and estradiol in the postmenopausal range per local normal range b) 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 estrogen-receptor positive and/or progesterone-receptor positive (>1%) early breast cancer by local laboratory. In case the receptor status from local pathology is unclear a central pathology review is obligatory. Results must be known prior to randomization.
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 analyzed tissue sample at initial diagnosis by a local laboratory).
Patients are eligible with completed (i.e., 5 years according to SoC), planned or ongoing adjuvant endocrine therapy, without any signs of distant relapse or secondary malignancy AND if primary diagnosis was 6 years or less before enrollment.
8a. Intermediate to high clinical or genomic risk, defined as either one of the following criteria:  c or p or ypN 2-3 with/without (neo)adjuvant chemotherapy;  in patients with c/ypN0-1:  non-pCR in patients with G3 or c/ypN1  high biological risk defined as G3 with Ki-67 ≥40%  or high genomic risk (RS>25 (known or Oncotype Dx® in screening phase) or another test)  high CTS5 score or UICC stage IIb (clinical if neoadjuvant chemotherapy or pathological) OR, if patients do not fulfill above criteria:  patients ≤50 years old or pre-/perimenopausal and c or (y)pN1 disease (in particular if ET-non-response or no chemotherapy)  patients >50 years old and postmenopausal and c or (y)pN1 with intermediate genomic risk (RS≥18) or non-low risk by another test OR 8b. Patients after isolated locoregional relapse with high-risk patterns (e.g., rpT2-3 or rpN1-3 or G3 or Ki-67 pre-treatment ≥20%), once surgery with free margins was completed OR 8c. Patients with any high clinical risk at Investigator´s assessment but not fulfilling above criteria
Completed primary therapy of breast cancer according to current guidelines, i.e., after (neo)adjuvant treatment, definite surgery and radiotherapy, if applicable.
No clinical evidence of distant metastasis (confirmation recommended prior to randomization by either combination of or either one of the following examinations: CT thorax / abdomen, chest X-ray, liver ultrasound, bone scan, PET-CT).
Patient has available tumor tissue from primary diagnostic biopsy.
No contraindication for adjuvant ET.
Eastern Cooperative Oncology Group (ECOG) performance status 0- 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, hemoglobin ≥ 8.0 g/dL, total bilirubin ≤ 1.5 ULN, except for patients with Gilbert’s Syndrome who may only be included if the total bilirubin is ≤ 2.0 × ULN or direct bilirubin within normal ranges, aspartate transaminase (AST) ≤ 3 × ULN, alanine transaminase (ALT) ≤ 3 × ULN, serum creatinine ≤ 1.5 x ULN.
Ability to swallow abemaciclib tablets or to administer other study medication, respectively.
Ability to communicate with the investigator and comply with study procedures.
Willing to receive therapy by clinical site, as required by the protocol.

cancel

Exclusion Criteria

Patient with distant metastases of breast cancer beyond regional lymph nodes.
Previously received CDK 4/6 inhibitor or patient with an indication for abemaciclib in the clinical routine per respective country: N 2-3 or N 1 and at least one of the following criteria: G3 or T3 and <14 months after primary diagnosis
Patient with a known hypersensitivity to any of the excipients of abemaciclib or standard-of-care endocrine therapy.
Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1 (polyneuropathy ≤ 2 or residual alopecia is allowed).
Patient has a concurrent malignancy or non-breast malignancy within 5 years prior to randomization.
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, diarrhea, malabsorption syndrome, or small-bowel resection).
Patient has any active systemic bacterial infection (requiring intravenous 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 any other concurrent severe and/or uncontrolled medical condition that, in the investigator´s judgment, could cause unacceptable safety risks, contraindicate patient participation in the clinical study, or compromise compliance with the protocol (e.g., interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g., estimated creatinine clearance <30ml/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, etc.).
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 is currently receiving any of the following substances, which cannot be discontinued 7 days prior to day 1 of study treatment: concomitant medications and herbal supplements, that are strong inducers or inhibitors of CYP3A4.
Participation in an investigational clinical trial AND being still under treatment with the investigational medicinal product, including the time until 30 days after last IMP treatment in the respective clinical trial.
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: a. total abstinence (when this is in line with the preferred and usual lifestyle of the patient), b. female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment, c. 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, d. placement of a non-hormonal intrauterine device (IUD), e. Use of condom + spermicide.
Use of oral (estrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormone replacement therapy.