First-in-Women Study Evaluating the Safety of Lutetium-177 Radioligand Therapy in Metastatic Triple-Negative Breast Cancer

Prior treatment

• Patient has known history of central nervous system (CNS) metastases. Exception: Patient with a history of CNS metastases who has received and completed therapy (e.g. surgery, radiotherapy), and is neurologically stable, asymptomatic and does not require corticosteroids or anti-convulsants to control neurological symptoms will be eligible. Discrete dural metastases are permitted but diffuse leptomeningeal disease is not. For patients with a history of CNS metastases, baseline imaging and subsequent radiological imaging for assessing treatment response must include MRI or ceCT evaluation of the brain.
• Patient has a single kidney or renal transplant or any concomitant nephrotoxic therapy that might put the patient at high risk of renal toxicity during the study in the judgement of the investigator.
• Patient received previously external beam irradiation to a field that includes more than 30% of the bone marrow or kidneys.
• Patient has received an investigational drug in another trial within the last 30 days.
• Patient had previous treatment with any of the following: PSMA-targeted radionuclide therapy, Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation.
• Patient has a bilateral hip replacement or any significant metallic implants or objects, which may in the opinion of the investigator, affect image quality and/or dosimetry calculations.

Other illness

• Patient has known hypersensitivity to the therapeutic IMP or diagnostic AxMP or any of their constituents.
• Patient shows presence of PSMA-negative disease: PSMA-negative disease defined as any PSMA-negative (lower uptake than blood pool using semiquantitative assessment (SUV measurement)) but FDG-or CT-positive lymph node >1 cm in the short axis and/or a PSMA-negative bone metastasis which has a significant soft tissue component suggesting ongoing disease activity and/or a PSMA-negative solid organ metastasis >1 cm in the long axis. Further details are provided in the Image Acquisition Guidelines (Fendler et al., 2023).
• Patient has diffuse marrow infiltration of disease (‘superscan’ appearance on full body 99mTc bone scan). A superscan is defined as bone scintigraphy in which there is excessive skeletal radioisotope uptake in relation to soft tissues along with absent or faint activity in the genitourinary tract and soft tissues due to diffuse bone/bone marrow metastases. Further details regarding this appearance are provided in the Image Acquisition Guidelines (Fendler et al., 2023)..
• Patient has known history of hematological malignancy.

Lab values

• Patient has any uncontrolled significant medical, psychiatric, or surgical condition or laboratory finding, that would pose a risk to patient safety or interfere with study participation or interpretation of individual patient results. For cardiac conditions, this includes, but is not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, and myocardial infarction diagnosed within 6 months prior to enrolment.
• Patient has ongoing treatment with bisphosphonates for bone-targeted therapy. Exception: Patients will be eligible if they have received a stable dose of Zoledronic acid for at least 8 weeks prior to enrolment. These patients must have had renal function monitored since initiation of bisphosphonate therapy, with a stable pattern observed, and must have an eGFR ≥ 60 mL/min.

Age

• Patient has known history of other solid malignancy that may reduce life expectancy and/or may interfere with disease assessment. Exception: Patients with histopathologically confirmed prior malignancy that has been treated, and who have been disease-free for >3 years. Patients with treated non-melanoma skin cancer and non-muscle invasive bladder cancer will be eligible.

Other

• Patient is not willing to take adequately safe contraceptive measures.
• Patient has an unresolved urinary tract obstruction defined as radiographic evidence of hydronephrosis with or without ureteric stent/nephrostomy. Exception: Where the clinical team judges that the patient’s hydronephrosis is not obstructing, and renal function meets the inclusion criteria, the patient may undergo 99mTc mercaptoacetyltriglycerine scanning during the screening period and if the result is non-obstructed, the patient can be eligible for the study.
• Patient has severe urinary incontinence that would preclude safe disposal of radioactive urine.
• Patient has clinically significant abnormalities on a single 12-lead electrocardiogram (ECG) at screening.
• Patient is a sponsor employees or investigator site personnel directly affiliated with this study, and their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
• Patient needs transfusion of blood products for the sole purpose of meeting the eligibility criteria for this clinical study.
• Patient is pregnant or breastfeeding.
• Patient is simultaneously participating in another clinical interventional trial.
• Patient is institutionalised due to official or court order.
• Patient has symptomatic spinal cord compression, or clinical or radiological findings that are indicative of impending spinal cord compression.

• Patient is female and ≥ 18 years old.
• Patient has at least 4 weeks or 5 half-lives (whichever is longer) elapsed between last anti-cancer treatment administration and the initiation of study treatment.
• Patient has all previous treatment-related toxicities to CTCAE version 6.0 grade of ≤3 resolved.
• Patient’s prior major surgery according to the European Surgical Association (ESA, Martin et al., 2020) must be at least 12 weeks away prior to study entry.
• Patient must have adequate bone marrow reserve and organ function as demonstrated by blood count, and serum biochemistry at baseline: − Platelets ≥ 100 × 10⁹/L − WBC ≥ 2.5 × 10⁹/L − Neutrophils ≥ 1.0 × 10⁹/L − Haemoglobin ≥ 9 g/dL − eGFR ≥ 50 ml/min/1,73 m² − Total bilirubin remains unchanged < 1.5 × ULN − AST/ALT < 3 × ULN − Albumin ≥ 30 g/L
• Patient is willing to provide signed and dated written informed consent form (ICF) prior to any study-specific procedures.
• Patient is willing to comply with required lifestyle restrictions following administration of the IMP per local regulations.
• Patient must have a life expectancy of at least 24 weeks from study entry in the assessment of the investigator.
• Patient must have a histologically confirmed diagnosis of TNBC. Patient must demonstrate HER-2 negative (IHC 0, 1+, or fluorescence in situ hybridization (FISH) negative and ER< 1%, and PR < 1%, per ASCO/CAP criteria).
• Patient must have locally recurrent or metastatic breast cancer and undergone ≥ 2 lines of therapy treatment and had progression or was intolerant of the latest treatment. Additionally, the available/suitable ADCs must have been applied if possible/applicable based on previous toxicities.
• Patient must exhibit an ECOG performance status of 0-2.
• Patient must have presence of disease target or non-target lesions (per RECIST v1.1) on CT/MRI and/or full body 99mTc bone scan performed within 6 weeks prior to screening.
• Patient must have a positive disease expression of PSMA as confirmed on PSMA PET/CT scan. Note: Positive disease is defined as having at least 1 PSMA-positive lesion of any size with higher uptake than bloodpool using semiquantitative assessment (SUV measurement). The lesion can be bone, lymph node or viscera. Further details regarding the interpretation of the diagnostic images can be found in the Image Acquisition Guidelines (Fendler et al., 2023).