A Phase I/​II, Dose Finding and Optimization Study of [177Lu]Lu-NeoB in Combination With Capecitabine in Patients With GRPR+, ER+, HER2- Metastatic Breast Cancer After Progression on Previous Endocrine Therapy in Combination With a CDK4/​6 Inhibitor. (NeoB-Cap1)

Intervention / Treatment 

Inclusion Criteria:

1. Signed informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment. must be obtained prior to participation in the study.
2. Participant is female or male adult ≥ 18 years old at the time of informed consent(s).
3. Participant has a histologically and/or cytologically documented diagnosisthe process of identifying a disease based on signs and symptoms, patient history and medical test results of ER+ breast cancer (ER expression >10% of tumor cell nuclei stain (regardless of PgR expression) (based on the most recently analyzed tissuea group of cells that work together to perform a function sample tested by a local laboratory).
4. Participant has HER2-negative (as per ASCO-CAP guidelines Wolff et al 2018) breast cancer defined as a negative in situ hybridization test (ISH) or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative ISH (e.g., FISH, CISH, or SISH) (based on the most recently analyzed tissue sample tested by a local laboratory) is required.

5a. Participant received no more than three prior endocrine therapies (single agent or in combination with targeted therapymedication that targets specific molecular features of cancer cells) regimen/s in the metastatic setting of which at least one included endocrine therapy in combination with a CDK4/6i. In addition:

• in case of confirmed presence of deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation, the participant may also have received a PARP inhibitor-based therapy.
• In case of HER2-low breast cancer (IHC 1+ or IHC 2+ with ISH negative as per ASCO-CAP guidelines Wolff et al 2023), the participant may also have received trastuzumab deruxtecan [Enhertu®]).6. Participant has metastatic breast cancer with radiologically confirmed progression of disease after the most recent therapy 7. Participant must have measurable disease, i.e., at least one measurable lesion as per RECIST 1.1. (a lesion at a previously irradiated site may only be counted as a target lesion if there is a clear sign of progression since the irradiation) as per local assessment.

Note: If only lytic bone lesions are present, they must have at least one lesion with a soft tissuetissue/the material that joins, holds up or surrounds inside body parts such as fat, muscle, ligaments and lining around joints component that can be evaluated by CT or MRI and meets the definition of measurability as per RECIST 1.1 criteria (participants with only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).

8a. Participant has at least one target lesion [as per RECIST 1.1 and based on the baseline stand-alone contrast-enhanced CT (or MRI)] with [68Ga]Ga-NeoB uptake greater than the physiological uptake of the liver at PET/CT or PET/MRI, as per local reading. In addition:

• Participants with liver or lung disease involvement must show [68Ga]Ga-NeoB uptake greater than the physiological uptake of the liver as follows:

• If there is liver disease involvement (in the absence of lung involvement), in ≥ 50% of all CT measurable liver lesions (RECIST 1.1)
• If there is lung disease involvement (in the absence of liver involvement), in ≥ 50% of all CT measurable lung lesions (RECIST 1.1)
• Participants with both liver and lung disease involvement must show [68Ga]Ga-NeoB uptake above the liver in ≥ 50% of all CT measurable lesions either in liver or lung (RECIST 1.1) and in at least one measurable lesion in the remaining organ (lung or liver) 9a. Participants with central nervous system (CNS) involvement are eligible provided that they meet ALL the following criteria:
• At least 2 weeks from prior therapy completion (including radiation and/or surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence) to initiation of the study treatment
• Clinically stable CNS tumor at the time of screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening
• Participant is not receiving steroids and/or anti-epileptic medications for brain metastases at the time of initiation of the radioligand study treatment 10. Participant has an Eastern Cooperative Oncologythe study, diagnosis and treatment of cancer Group (ECOG) performance status of 0 or 1.11. Participant has adequate bone marrowsoft, spongy tissue found in bones that makes blood cells and organ function as defined by the following laboratory values (as assessed by local laboratory):
• Absolute neutrophil count ≥ 1.5 × 109/L
• Plateletssmall disc-shaped blood cells that clump together to form clots to stop bleeding ≥ 100 × 109/L
• Hemoglobin ≥ 9.0 g/dL
• International Normalized Ratio (INR) ≤1.5
• Creatinine Clearance ≥60 mL/min using the Chronica long-lasting disease that changes slowly over time Kidneya pair of bean-shaped organs in the abdomen that are responsible for filtering excess water and waste products from the blood and converting them into urine to be removed from the body Disease Epidemiology Collaboration (CKD-EPI) equation
• Total bilirubin (TBIL) < 1.5 × ULN (any elevated bilirubin should be asymptomatic at enrollment) except for participants with Gilbert’s syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN
• In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN. If the participant has liver metastases, the participant will be eligible for the study if ALT and AST < 5 X ULN.
• Serum lipase ≤ 1.5 × ULN Note: no platelet transfusion, packed red bloodthe red bodily fluid that transports oxygen and other nutrients around the body cell transfusion, or G-CSF will be allowed during the screening phase after ICF signature
• Participant must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication:
• Potassium
• Magnesium
• Total Calcium (corrected for serum albumin) 12. Participant must be able to swallow capecitabine tablets. 13. Participant must be able to communicate with the investigator and comply with the requirements of the study procedures.14a. For Phase I part only Female participant must be in postmenopausal status at the time of starting study treatment.

Postmenopausal status is defined by any of the following (NCCN 2024):

• Prior surgical bilateralaffecting both sides oophorectomy (with or without hysterectomycomplete or partial removal of the uterus)
• Age ≥ 60 years
• Age < 60 years and ≥ 12 months of natural (spontaneous) amenorrhea in the absence of chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells, tamoxifen, toremifene, or ovarian suppression with serum Follicle-Stimulating Hormonea chemical substance produced by glands in the endocrine system that regulates various functions in the body (FSH) and estradiol in the postmenopausal range per local normal range.
• Aged < 60 years: chemotherapy-induced amenorrhea for ≥ 12 months with serial measurements of FSH and estradiol in post-menopausal ranges (NCCN V4 2023).
• Aged < 60 years: on tamoxifen with serial measurements of FSH and estradiol in post-menopausal ranges Note: Ovarian radiation or treatment with a gonadotropin releasing hormone agonist (GnRHas e.g. goserelin acetate) is not permitted for induction of ovarian suppression in the Phase I part.

Male participants, provided that they do not require continued GnRHas while on study treatment 15a. For Phase II part only

• Female participant is post-menopausal as per criteria above at the time of starting study treatment.

OR • Female participant is pre/peri-menopausal at the time of starting study treatment

Pre-menopausal status is defined as either:

• Patient had last menstrual period within the last 12 months OR
• If on tamoxifen or toremifene within the past 14 days, FSH and estradiol in pre-menopausal ranges on serial measurements OR
• In case of therapy induced amenorrhea, FSH and estradiol in pre-menopausal ranges on serial measurements Note: Peri-menopausal status is defined as neither pre-menopausal nor post-menopausal (see definition above)
• Male participants, regardless of their need of GnRHas while on study treatment.