Phase II neoadjuvant study evaluating capivasertib plus fulvestrant vs fulvestrant in patients with primary high-risk lobular breast cancer- LOBSTER

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GBG Forschungs GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Nov 2024 → ongoing

Decision date (initial)

2024-05-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Therapy, Safety

To assess complete cell cycle arrest (CCCA).

Secondary objectives 4

1. To assess safety and tolerability.
2. To assess breast conservation rate (BCS)
3. To assess pathological complete response rate (pCR) by different definitions
4. To assess invasive disease-free survival (iDFS) and overall survival (OS) by referring to data from GBG patient’s registry

Conditions and MedDRA coding

primary high-risk lobular breast cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 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.
2. 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
3. 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.
4. Willingness and ability to provide archived formalin fixed paraffin embedded (FFPE) tissue block from core biopsy before the start of neoadjuvant therapy.
5. 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.
6. 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).
7. No clinical evidence of distant metastases.
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
9. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.
10. The patient must be accessible for scheduled visits, treatment, and follow-up.
11. Normal cardiac function must be confirmed according to local guidelines.
12. 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).
13. Complete staging work-up prior to the initiation of neoadjuvant therapy as per standard recommendations.

Exclusion criteria 20

1. Female patients of childbearing potential.
2. Excisional biopsy or lumpectomy for the current disease performed prior to study entry.
3. psilateral surgical axillary staging procedure including sentinel lymph node biopsy prior to randomization. Exceptions: FNA or core biopsy of an axillary lymph node.
4. Any previous treatment including endocrine therapy, chemotherapy, radiotherapy or targeted therapy (including AKT inhibitor or PIK3 inhibitor) for the currently diagnosed breast cancer.
5. Concurrent use of herbal or natural products intended as treatment or prophylaxis for any type of cancer.
6. Known hypersensitivity reaction to one of the compounds or substances used in this protocol.
7. Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John’s wort).
8. 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.
9. Any contraindication for fulvestrant.
10. Patients with definitive clinical or radiologic evidence of stage IV cancer (metastatic disease) are not eligible.
11. 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.
12. History of type I or type II diabetes mellitus requiring insulin.
13. 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.
14. Known medically history of HIV infection, tuberculosis, or hepatitis B.
15. 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.
16. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving therapy.
17. History of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures that would prohibit the understanding and giving of informed consent.
18. 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).
19. 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.
20. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint CCCA is defined as Ki67 drop to <2.7% after approximately 10 weeks (will be assessed centrally on the breast tissue submitted to central pathology)

Secondary endpoints 5

1. Pathological complete response (pCR ypT0 ypN0) is defined as no microscopic evidence of residual invasive and non-invasive viable tumor cells in all resected specimens of the breast and axilla.
2. Pathological complete response (pCR ypT0/is ypN0) is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla.
3. Pathological response will be assessed considering histological reports of all removed breast and lymphatic tissues from all surgeries; patients in whom pCR cannot be assessed will be counted as no pCR.
4. Invasive disease-free survival (iDFS) is defined as time from randomization until first iDFS event: local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause.
5. Overall survival OS is defined as time from randomization until death due to any cause.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GBG Forschungs GmbH

Sponsor organisation

GBG Forschungs GmbH

Address

Dornhofstrasse 10

City

Neu-Isenburg

Postcode

63263

Country

Germany

Scientific contact point

Organisation

GBG Forschungs GmbH

Contact name

Medicine and Research

Public contact point

Organisation

GBG Forschungs GmbH

Contact name

Medicine and Research

Third parties 4

Locations

1 EU/EEA country · 33 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications