Phase Ib/IIa Dose Escalation and Expansion Study of [²¹²Pb]Pb-ADVC001 in Metastatic Castration Resistant Prostate Cancer (TheraPb - Phase I/II Study).

This is a prospective, open-label, non-randomised, dose-escalation and expansion study. The study aims to determine the safety and tolerability of escalating doses of \[²¹²Pb\]Pb-ADVC001 administered every 4 or every 2 weeks during the dose finding phase (Phase 1b), and then aims to assess the efficacy and safety of \[²¹²Pb\]Pb-ADVC001 at the RP2D in 3 participant groups in the expansion phase (Phase 2a).


Eligibility Criteria:
Inclusion Criteria:

* Be willing and able to provide written informed consent for the trial.
* Adults aged 18 years or older at the time of consent.
* Has documented metastatic adenocarcinoma of the prostate, confirmed by histopathology.
* Has metastatic disease (≥ 1 metastatic lesion present on baseline CT, magnetic resonance imaging \[MRI\] or bone scintigraphy scan).
* Has castration-resistant prostate cancer progressing or has progressed on androgen receptor therapy and must have castrate level of serum/plasma testosterone (≤ 50 ng/dL or ≤ 1.7 nmol/L).
* Has disease that is progressing at Screening, despite a castrate testosterone level (≤ 50 ng/dL or ≤ 1.7 nmol/L), by the demonstration of at least one of the following:

  1. Increase in PSA greater than 25% and \> 2 ng/mL above nadir, confirmed by progression at 2 timepoints at least 3 weeks apart
  2. Progressive disease or new lesion(s) (relative to previous imaging) in the viscera or lymph nodes as per the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 or in bone as per Prostate Cancer Working Group 3 (PCWG3). Any ambiguous results are to be confirmed by additional imaging modality (e.g., CT or MRI, Tc 99m bone scintigraphy).
* a. For Phase 1b Dose Escalation: Exposure to at least one ARPi and taxane-based chemotherapy at any time in the course of their disease (unless taxanes considered contraindicated or declined by participant).

  b. For Phase 2a Expansion Group 1: Exposure to at least one ARPi at any time in the course of their disease and received taxane-based chemotherapy for the treatment of mCRPC.

  c. For Phase 2a Expansion Group 2: Has had exposure to at least one ARPi at any time in the course of their disease and has not received a taxane for the treatment of mCRPC. Participants may have received a taxane-based therapy in the (neo)adjuvant or mHSPC setting at least 12 months prior to first treatment cycle (C1D1).

  d. For Phase 2a Expansion Group 3: Has had exposure to ¹⁷⁷Lu-PSMA at any time in the course of their disease.
* Has disease that is prostate specific membrane antigen (PSMA) positive, as demonstrated by ⁶⁸Ga-PSMA-PET/CT or ¹⁸F-based PSMA PET/CT and confirmed as eligible by local reader. PSMA-positive participants are defined as those having at least one tumor lesion with ⁶⁸Ga- or ¹⁸F- PSMA PET CT uptake greater than normal liver (based on visual assessment) and all tumor lesions larger than size criteria with ⁶⁸Ga- or ¹⁸F-PSMA uptake greater than liver \[short axis size criteria: organs ≥ 1 cm, lymph nodes ≥ 2.5 cm, bones (soft tissue component) ≥ 1 cm\].
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
* Has adequate renal, haematological, and liver function, as defined by the following safety laboratory results at Screening
* Estimated life expectancy \> 6 months.
* Has the capacity to understand the study and be willing and able to comply with all study requirements, including the timing and nature of all required assessments.
* Must agree to comply with the radiation protection guidelines (including hospital admissions and isolation, where relevant) that are applied by the treating institution.
* Must agree to practice adequate precautions to prevent pregnancy in a partner to avoid potential problems associated with radiation exposure to the unborn child.

Exclusion Criteria:

* Has prostate cancer with known significant sarcomatoid or spindle cell or neuroendocrine small cell components, as determined by the Investigator. Participants with minor sarcomatoid, spindle cell or neuroendocrine small cell prostate cancer, but otherwise PSMA-expressing disease, may be eligible at the discretion of the Investigator.
* Has symptomatic dry eye, symptomatic dry mouth, Sjogren's syndrome or other pathologies affecting salivary gland function.
* Has received prior treatment with radiopharmaceuticals containing the following radioisotopes: lutetium-177, actinium-225, strontium-89, samarium-153, rhenium-186, rhenium-188, or other lead-212-containing radiopharmaceuticals. Note: prior radium-223 exposure is not exclusionary, and prior exposure to ¹⁷⁷Lu-PSMA is not exclusionary for Group 3 participants in Phase 2a Expansion, provided treatment ceased at least 12 weeks prior to first treatment cycle (C1D1).
* Has received systemic anti-cancer therapy other than ADT and ARPi (e.g., chemotherapy, immunotherapy, or biological therapy) and/or radiation therapy within four weeks of first study cycle. Participants will not be eligible if any significant adverse events related to prior systemic anti-cancer therapy have not resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) ≤ Grade 2 at the time of Screening, even if the systemic therapy ceased greater than four weeks prior to first treatment cycle (C1D1).
* Has received any investigational agent within four weeks of first treatment cycle (C1D1).
* Has concurrent other malignancies that are expected to alter life expectancy or may interfere with disease assessment. Participants with a prior history of malignancy that has been adequately treated and who have been disease-free for more than three years are eligible, as are participants with adequately treated non-melanoma skin cancer, and those with non-muscle invasive bladder cancer.
* Has known brain metastases of any size or has a single hepatic metastasis \> 1 cm (longest diameter), or more than one hepatic metastases of any size.
* Has symptoms of spinal cord compression or impending spinal cord compression.
* Has diffuse bone-marrow involvement, i.e. "superscan", defined as bone scintigraphy in which there is excessive skeletal radioisotope uptake \[\>20 bone lesions\] in relation to soft tissues, along with absent or faint activity in the genitourinary tract due to diffuse bone/bone marrow metastases).
* Has a serious active or sub-clinical infection, or angina pectoris, or heart failure (New York Heart Association \[NYHA\] Class III or IV), or significantly prolonged QT interval, or other serious illness involving the cardiac, respiratory, central nervous system, renal, hepatic or haematological organ systems, which might impair the ability to participate in this study to the full extent, or which may require treatment that could interact with study treatment. Note: participants with renal obstruction of any degree may be eligible to participate at the discretion of the Investigator.
* Evidence of untreated urinary tract obstruction (e.g., hydroureter or hydronephrosis). Participants who undergo a successful decompressive procedure prior to treatment will not be excluded. Note: participants with renal obstruction of any degree may be eligible to participate at the discretion of the Investigator.
* Has a known alteration in breast cancer genes (BRCA) BRCA1, BRCA2 or Ataxia Telangiectasia Mutated Gene (ATM), and are eligible to receive olaparib therapy according to their treating institution standard of care.
* Has severe claustrophobia or other condition (e.g., pain) that may impact the ability to comply with the imaging aspects of this protocol.