Overview

This study is designed to investigate the safety, tolerability, and effectiveness of a new treatment called AB001 in both 177Lu-PSMA naïve and 177Lu-PSMA experienced patients with advanced prostate cancer. AB001 targets a specific protein found on prostate cancer cells called prostate specific membrane antigen (PSMA) and delivers radioactive particles to kill the cancer cells.

The primary goal of the study is to determine the safety profile of AB001 and how well patients tolerate the treatment. Researchers also aim to identify the best dose and schedule for further testing and clinical development.

AB001 could be a promising treatment because it uses alpha particles, which are highly effective at damaging cancer cells while causing minimal harm to surrounding healthy tissue. This targeted approach is expected to result in fewer side effects compared to other types of radiation therapy.

This Phase 1 study consists of two main parts: dose escalation and dose expansion. In the first part, researchers will test different doses of AB001 to find the safest and most effective dose. In the second part, the selected dose will be further evaluated to refine the treatment schedule and gather more data on its effectiveness and safety.

The study aims to provide early data on the anti-tumour activity of AB001 and determine the best dose and treatment schedule for future trials. Researchers hope that AB001 will offer a new and effective treatment option for patients with advanced prostate cancer.

Eligibility

Inclusion Criteria:

• Male participants at least 18 years of age at the time of the signing informed consent
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1
• Progressive mCRPC with histological confirmation of prostate adenocarcinoma
• Previous treatment with at least one novel ARPI.
• Prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum testosterone (<50 ng/dL or <1.7 nmol/L).
• Prior treatment with at least one taxane regimen or patient refusing or considered appropriate by treating physician to delay taxane therapy
• 177Lu-PSMA experienced Group only: Prior treatment with at least one dose of 177Lu-PSMA greater than 6 weeks from start of study treatment.
• At least one PSMA-avid distant metastatic lesion (defined as physiological uptake greater than that of liver parenchyma ) and no PSMA negative lesions (defined as physiological uptake equal to or lower than that of liver parenchyma in any lymph node with a short axis of at least 2.5 cm, in any solid organ lesion with a short axis of at least 1.0 cm, or in any bone lesion with a soft tissue- component of at least 1.0 cm in the short axis) confirmed by PSMA -PET/CT with a permitted PSMA-targeting imaging agent within 28 days before start of study treatment
• Adequate bone marrow, renal, and hepatic function, as assessed by the following laboratory requirements within 28 days before start of study treatment:
  1. Absolute neutrophil count ≥1.5 × 109/L.
  2. Haemoglobin ≥9.0 g/dL.
  3. Platelet count ≥100 × 109/L.
• eGFR ≥60 mL/min/1.73m2, according to the Modified Diet in Renal Disease (MDRD)

  abbreviated formula.

  1. Total bilirubin ≤1.5 × ULN (except if confirmed history of Gilbert's disease, in which case direct bilirubin must be normal).
  2. ALT and AST <2.5 × ULN (≤5 × ULN for participants with liver involvement).
• Male participants must agree to use highly effective contraception during treatment

  and for three months after the last study treatment and refrain from donating sperm during this period. Contraceptive use should be consistent with local regulations regarding methods of contraception for those participating in clinical studies.

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria

• Urinary obstruction, or where there is deemed a substantial risk of urinary obstruction due to pelvic disease.
• Untreated central nervous system (CNS) metastases (therapy includes surgery, radiotherapy, gamma knife) or treated CNS metastases which are not adequately controlled. Treated CNS metastases are permitted provided they are neurologically stable, asymptomatic, and corticosteroids are not required to maintain neurologic integrity.
• Symptomatic medullary cord compression, or clinical or radiologic findings indicative of impending cord compression.
• Diffuse bone or bone-marrow involvement i.e., a "superscan": defined as bone scintigraphy in which there is diffuse and intense activity throughout the axial skeleton, relative to soft-tissue, due to metastatic disease. Participants with borderline/ambiguous assessment may be included on a case-by-case basis on agreement with the Investigator and Sponsor.
• History of myelodysplastic syndrome (MDS), treatment-related acute myeloid leukaemia or features suggestive of MDS/acute myeloid leukaemia.
• A known additional malignancy that has required active treatment within the past two years before start of study treatment, except for adequately treated basal or squamous cell carcinoma of the skin, or carcinoma in situ that has undergone curative therapy.
• Active clinically serious infections of CTCAE Grade >2, or Grade 2 infections not responding to therapy.
• Human immunodeficiency virus (HIV) infection with any of the following: a cluster of differentiation 4 positive (CD4+) T- cell count of <350 cells/μL; a history of acquired immune deficiency syndrome (AIDS) defining opportunistic infection within the past 12 months; established on stable antiretroviral therapy for less than four weeks; a HIV viral ribonucleic acid (RNA) level >400 copies/mL; requiring either antiretroviral therapy prophylactic antimicrobials expected to cause significant drug-drug interactions or overlapping toxicities.
• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Participants with chronic HBV or HCV infection are eligible provided the infection has been controlled with appropriate treatment and the viral load is below the limit of quantification.
• Serious, infected non-healing wound, ulcer, or bone fracture.
• Major surgery, open biopsy, or significant trauma within four weeks before start of study treatment.
• Impaired cardiac function or clinically significant cardiac disease, including: congestive heart failure (New York Heart Association [NYHA] Class II, III, or IV); unstable angina, new-onset angina (within three months of start of study treatment), myocardial infarction less than six months before the start of study treatment; clinically significant arrhythmia; uncontrolled hypertension (systolic blood pressure >140 mmHg and/or diastolic blood pressure >100 mmHg); prolonged QTc interval (> 470 ms).
• Known allergies, hypersensitivity, or intolerance to the study treatment (including excipients).
• Prior systemic anticancer therapy (e.g., chemotherapy, immunotherapy, or biological therapy [including mAbs]) or investigational therapy within four weeks before the start of study treatment, with the exception of luteinizing hormone-releasing hormone (LHRH) agonists/antagonists or gonadotropin-releasing hormone (GnRH) agonists/antagonists. Start of study treatment is allowed in shorter timeframes provided five half-lives of the prior agents(s) have elapsed.
• Previous PSMA-targeted radiopharmaceutical treatment, except:
  1. Participants who received only a micro-dose of AB001 (i.e., 212Pb-NG001) in a Phase 0 study.
  2. 177Lu-PSMA experienced participants must have had prior treatment with at least one dose of 177Lu-PSMA; this must have ended at least six weeks before the start of study treatment.
• Prior treatment with any other systemic radiopharmaceutical therapy within a

  clinical trial with the exception of bone targeting agents based on 223Ra and 177Lu-PSMA therapy (as above). For participants who have had prior treatment with 223Ra bone targeted agents, treatment must have ended at least six months before the start of study treatment.

• Prior definitive radiotherapy completed less than six weeks before the start of study treatment; palliative radiotherapy for symptom control within this time is allowed on agreement between the Investigator and medical monitor provided (i) no more than 10% of the participants' bone marrow is irradiated, and (ii) it does not encompass all potential target/measurable lesions for participants in dose expansion
• Prior EBRT where dose to a critical organ (e.g., kidneys, heart, lung) has exceeded the EBRT normal organ tolerance dose limit.
• Ongoing toxicity CTCAE Grade ≥2 due to prior anti-cancer therapy that is significant or not stabilised (including clinically significant dry eyes or dry mouth (xerostomia)). Chronic toxic effects Grade ≤2 where no further resolution is expected do not require exclusion (e.g., chemotherapy-induced neuropathy, fatigue, alopecia, anorexia, and so forth).
• Live vaccines within four weeks before the start of study treatment; vaccines for coronavirus disease 2019 (COVID-19) are allowed.
• Biological response modifiers, such as granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and erythropoietin within three weeks before start of study treatment. Chronic use of erythropoietin is allowed, provided there is no dose modification within three weeks before the start of study treatment.
• Transfusion for the sole purpose of making a subject eligible for study inclusion.
• Systemic corticosteroids >10 mg of prednisone/prednisolone per day or herbal products that may decrease PSA levels (e.g., saw palmetto) within four weeks before the start of study treatment.
• Concurrent participation in the active part of another clinical study with investigational product(s).
• Any condition which in the opinion of the Investigator would preclude the participants' study participation, impair their ability to comply with the protocol requirements or impair the scientific validity of the study.