Phase II Neoadjuvant Evaluation of Capivasertib and Fulvestrant Versus Fulvestrant in Primary High-Risk Lobular Breast Cancer

Trial ID: 2023-509292-17-00
Protocol: GBG 118
Sponsor: GBG Forschungs GmbH

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Diseases & Conditions

Invasive lobular breast carcinoma

Objectives

The primary objective of this Phase II neoadjuvant study is to assess **complete cell cycle arrest (CCCA)** in patients with primary high-risk lobular breast cancer. Evaluating CCCA is clinically relevant as it provides insight into the efficacy of the treatment regimen in halting cancer cell proliferation, which is crucial for improving patient outcomes.

Secondary objectives include:

To assess safety and tolerability, ensuring that the treatment is manageable for patients.
To evaluate the breast conservation rate (BCS), which is important for determining the potential for less invasive surgical options.
To assess the pathological complete response rate (pCR) by different definitions, providing a measure of the treatment's effectiveness in eradicating cancer cells.
To evaluate invasive disease-free survival (iDFS) and overall survival (OS) by referring to data from the GBG patient’s registry, which are critical endpoints for understanding long-term treatment benefits.

Participants

The clinical trial focuses on **postmenopausal women** diagnosed with **primary high-risk lobular breast cancer**. The study population includes females aged 18 years and older, with no male participants involved. Participants are required to have a centrally confirmed diagnosis of HER2-negative and HR-positive disease, with a Ki67% greater than 10%. The trial excludes individuals with clinical evidence of distant metastases and those with an Eastern Cooperative Oncology Group (ECOG) performance status greater than 1. Participants must have an estimated life expectancy of at least five years, regardless of their breast cancer diagnosis. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. Selection criteria include normal cardiac function, specific laboratory requirements, and the ability to provide archived tissue samples. The trial population was selected based on these criteria to ensure the study's objectives are met effectively.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **capivasertib** in combination with **fulvestrant** versus fulvestrant alone in patients with primary high-risk lobular breast cancer. The trial aims to assess complete cell cycle arrest (CCCA) as the primary endpoint, defined by a Ki67 drop to less than 2.7% after approximately 10 weeks. Secondary endpoints include pathological complete response and invasive disease-free survival. The trial is expected to commence recruitment on July 15, 2024, and conclude by October 15, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as postmenopausal status, normal cardiac function, and laboratory parameters. Following randomization, participants will receive either the investigational combination therapy or the control treatment. Study visits will include regular assessments to monitor safety, efficacy, and adherence to the treatment regimen. Follow-up visits will occur at specified intervals to evaluate the primary and secondary endpoints, with the end-of-study visit marking the completion of the participant's involvement.

The expected duration of participant involvement is approximately 10 weeks, corresponding to the treatment period. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or any significant protocol deviations. Participants will be monitored closely throughout the trial to ensure compliance with the study protocol and to address any safety concerns promptly.

Treatment

The clinical trial involves the administration of **Faslodex**, a pharmaceutical product containing the active substance **fulvestrant**. Faslodex is provided as a **solution for injection** and is administered via the **intramuscular** route. The dosage for Faslodex is 500 mg, with a maximum daily and total dose of 500 mg. The treatment period is set for a maximum of 10 days. Fulvestrant acts as a competitive estrogen receptor (ER) antagonist, and its chemical origin is confirmed. The product is manufactured by AstraZeneca AB and holds the marketing authorization number EU/1/03/269/001.

In addition to Faslodex, the trial also includes the administration of **Capivasertib**, which is provided in the form of a **film-coated tablet**. Capivasertib is administered **orally** with a maximum daily and total dose of 800 mg. The treatment duration is also limited to 10 days. Capivasertib functions as a potent and selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. This product is also of chemical origin and is produced by AstraZeneca AB. The trial aims to evaluate the efficacy of these treatments in patients with primary high-risk lobular breast cancer, focusing on achieving complete cell cycle arrest (CCCA).

Efficacy

The efficacy of the clinical trial will be assessed through a series of predefined endpoints. The primary endpoint is the assessment of **Complete Cell Cycle Arrest (CCCA)**, which is defined as a reduction in Ki67 levels to less than 2.7% after approximately 10 weeks. This will be centrally evaluated on breast tissue submitted to central pathology. Secondary endpoints include the evaluation of pathological complete response (pCR), which is characterized by the absence of microscopic evidence of residual invasive and non-invasive viable tumor cells in all resected specimens of the breast and axilla. This includes two specific definitions: pCR ypT0 ypN0 and pCR ypT0/is ypN0. Additionally, invasive disease-free survival (iDFS) will be measured from the time of randomization until the first iDFS event, which includes local invasive recurrence, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer, or death from any cause. Overall survival (OS) will also be assessed, defined as the time from randomization until death due to any cause. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the effectiveness of the treatment regimen in patients with primary high-risk lobular breast cancer.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and followup, and documented according to the local regulatory requirements.
Postmenopausal women with age at diagnosis ≥ 18 years. Postmenopausal status is defined as: • Age ≥ 60 years • Age <60 years and amenorrhea for at least 12 continuous months with no identified cause other than menopause • Bilateral oophorectomy Negative pregnancy test (urine or serum) within 14 days prior to randomization for all postmenopausal women 50 years of age or younger without bilateral oophorectomy
Unilateral or bilateral primary untreated lobular invasive carcinoma of the breast. In case of multifocal, multicentric or bilateral breast cancer, all biopsied lesions must be lobular; the lead tumor has to be defined by the investigator based on the inclusion criteria for the respective subtype and the risk status. Lobular histology has to be centrally confirmed.
Willingness and ability to provide archived formalin fixed paraffin embedded (FFPE) tissue block from core biopsy before the start of neoadjuvant therapy.
Centrally confirmed HER2-negative (IHC score 0-1+, or 2+ and ISH negative according to ASCO/CAP guideline) and HR-positive (≥10% positive stained cells) disease, assessed on the core of diagnostic biopsy. Ki67% >8% is required. In case of bilateral breast cancer, HER2-negative, HR-positive and lobular histology status has to be confirmed for both sides.
Patients with invasive lobular breast cancer at high risk for recurrence defined as cT1c and clinical nodal involvement (cN+) or ≥ cT2 disease (irrespective of nodal involvement).
No clinical evidence of distant metastases.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.
The patient must be accessible for scheduled visits, treatment, and follow-up.
Normal cardiac function must be confirmed according to local guidelines.
Laboratory requirements: Hematology • Absolute neutrophil count (ANC) ≥1.5 x 109 / L • Platelets ≥100 x 109 / L • Hemoglobin ≥10 g/dL (≥6.2 mmol/L) Hepatic function • Total bilirubin <1.25x ULN • AST and ALT <=1.5x ULN • Alkaline phosphatase <=2.5x ULN Glucose Metabolism • HbA1c <8.0% (63.9 mmol/mol) Renal Function • Creatinine <1.25x ULN or creatinine clearance ≥50 ml/min (if creatinine is above ULN according to Cockroft-Gault).
Complete staging work-up prior to the initiation of neoadjuvant therapy as per standard recommendations.

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Exclusion Criteria

Female patients of childbearing potential.
Excisional biopsy or lumpectomy for the current disease performed prior to study entry.
psilateral surgical axillary staging procedure including sentinel lymph node biopsy prior to randomization. Exceptions: FNA or core biopsy of an axillary lymph node.
Any previous treatment including endocrine therapy, chemotherapy, radiotherapy or targeted therapy (including AKT inhibitor or PIK3 inhibitor) for the currently diagnosed breast cancer.
Concurrent use of herbal or natural products intended as treatment or prophylaxis for any type of cancer.
Known hypersensitivity reaction to one of the compounds or substances used in this protocol.
Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John’s wort).
Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of capivasertib.
Any contraindication for fulvestrant.
Patients with definitive clinical or radiologic evidence of stage IV cancer (metastatic disease) are not eligible.
Patients with a history of any malignancy are ineligible with the following exceptions: • Patient has been disease-free for at least 5 years and is at low risk for recurrence of that malignancy except for ipsilateral invasive breast cancer. • CIS of the cervix, basal cell and squamous cell carcinomas of the skin.
History of type I or type II diabetes mellitus requiring insulin.
Severe and relevant co-morbidity that would interact with the application of study drugs or the participation in the study, including cerebrovascular incident including transient ischemic attack, or symptomatic pulmonary embolism, active infection requiring intravenous anti -microbial treatment (antibiotics, anti-fungal, and anti-viral drugs) within 1 week of enrolment. Patients with confirmed Gilbert’s syndrome may be included in the study.
Known medically history of HIV infection, tuberculosis, or hepatitis B.
History of and/or active cardiac disease that would preclude the use of study treatments. This includes but is not confined to any of the following cardiac criteria: • Clinically significant cardiac dysfunction including heart failure (NYHA II-IV), active ventricular arrhythmias requiring medication or arrhythmias requiring a pacemaker, and history of a myocardial infarction within 6 months prior to randomization, angina pectoris, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, angioplasty, or vascular stent. • Mean resting QT interval corrected by Fridericia’s formula (QTcF) >470 msec obtained from triplicate ECGs. • Increased risk of QTc prolongation or risk of arrhythmic events such as heart failure, uncontrolled electrolyte disorders (e.g., hypocalcemia, hypokalemia, or hypomagnesemia), potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age, or any concomitant medication known to prolong the QT interval.
Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving therapy.
History of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures that would prohibit the understanding and giving of informed consent.
Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension or hypotension (BP <50mmHg), significant aneurysm, renal transplant and active bleeding diseases).
Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
Participation in another clinical study with a study intervention or investigational medicinal device administered in the 4 weeks prior to first dose of study intervention or concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.