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

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 byhistopathology.

• Has metastatic disease (≥ 1 metastatic lesion present on screening CT, magneticresonance imaging [MRI] or bone scintigraphy scan).

• Has castration-resistant prostate cancer progressing or has progressed on androgenreceptor therapy with castrate level of serum/plasma testosterone (≤ 50 ng/dL or ≤ 1.7 nmol/L). Progression at screening demonstrated by at least one of the following:

1. Increase in PSA greater than 25% and > 2 ng/mL above nadir, confirmed byprogression at two timepoints at least three weeks apart

2. Progressive disease or new lesion(s) (relative to previous imaging) in theviscera or lymph nodes as per the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 or in bone as per Prostate Cancer Clinical Trials Working Group 3 (PCWG3). Any ambiguous results are to be confirmed by additional imagingmodality (e.g., CT or MRI, Tc99m bone scintigraphy).

• For Phase 1b Dose Escalation: Exposure to at least one ARPi and taxane-basedchemotherapy at any time in the course of their disease (unless taxanes consideredcontraindicated or declined by participant as documented in the patient's sourcedocuments and eCRF).

• For Phase 2a Expansion Group 1: Has had exposure to at least one ARPi at any time inthe course of their disease.Has received at least one line of taxane-basedchemotherapy for the treatment of mCRPC. Has not had exposure to ¹⁷⁷Lu-PSMA.

• For Phase 2a Expansion Group 2: Has had exposure to at least one ARPi at any time inthe course of their disease. Has not received a taxane for the treatment of mCRPC.Note, participants may have received a taxane-based therapy in the (neo)adjuvant ormHSPC setting at least 12 months prior to C1D1. Has not had exposure to ¹⁷⁷Lu-PSMA.

• For Phase 2a Expansion Group 3: Has had exposure to at least one ARPi at any time inthe course of their disease. Has had exposure to 177Lu-PSMA at any time in thecourse of their disease.

• Has disease that is prostate specific membrane antigen (PSMA) positive, asdemonstrated by ⁶⁸Ga-PSMA-PET/CT or ¹⁸F-based PSMA PET/CT and confirmed as eligibleby local reader. PSMA-positive participants are defined as those having at least onetumour lesion with ⁶⁸Ga- or ¹⁸F- PSMA PET CT uptake greater than normal liver (basedon visual assessment) and all tumour lesions larger than size criteria with ⁶⁸Ga- or ¹⁸F-PSMA uptake greater than liver [short axis size criteria: organs ≥ 1 cm, lymphnodes ≥ 2.5 cm, bones (soft tissue component) ≥ 1 cm].

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.

• Has adequate haematological, renal, and liver function, as defined by safetylaboratory results at Screening.

• Estimated life expectancy > 6 months.

• Has the capacity to understand the study and be willing and able to comply with allstudy requirements, including the timing and nature of all required assessments.

• Agrees to comply with the radiation protection guidelines (including hospitaladmissions and isolation, where relevant) that are applied by the treatinginstitution.

• Agrees to practice adequate precautions to prevent pregnancy in a partner to avoidpotential problems associated with radiation exposure to the unborn child.

Exclusion Criteria:

• Has prostate cancer with known significant sarcomatoid or spindle cell orneuroendocrine small cell components, as determined by the Investigator.Participants with minor sarcomatoid, spindle cell or neuroendocrine small cellprostate cancer, but otherwise PSMA-expressing disease, may be eligible at thediscretion of the Investigator.

• Has symptomatic dry eye, symptomatic dry mouth, Sjogren's syndrome or otherpathologies affecting salivary gland function.

• Has received prior systemic radioligand therapy. Note, prior radium-223 exposure isnot exclusionary. Prior exposure to 177Lu-PSMA is required for Group 3 participantsin Phase 2a Expansion, provided treatment ceased at least 12 weeks prior to C1D1.

• Has received systemic anti-cancer therapy and/or radiation therapy within four weeksof C1D1 or has received any investigational agent within four weeks of C1D1. Note,patients should continue on androgen deprivation therapy. Prior ARPi therapy doesnot require washout prior to C1D1.

• Participants will not be eligible if any significant adverse events related to priorsystemic anti-cancer therapy have not resolved to National Cancer Institute CommonTerminology Criteria for Adverse Events (NCI CTCAE version 5.0) Grade ≤ 2 at thetime of Screening, even if the systemic therapy ceased greater than four weeks priorto C1D1.

• Has malignancies other than prostate cancer within 3 years prior to enrolment,except for those with a negligible risk of metastases (e.g expected 5-year-overall-survival >90%) treated with expected curative outcome.

• Has known CNS metastases of any size.

• Has symptoms of spinal cord compression or impending spinal cord compression.Patients with prior treatment for spinal cord compression should be clinicallystable off steroids for at least 4 weeks.

• Has diffuse bone-marrow involvement, i.e, "superscan", defined as bone scintigraphyin which there is excessive skeletal radioisotope uptake (>20 bone lesions) inrelation to soft tissues, along with absent or faint activity in the genitourinarytract 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 QTinterval, or other serious illness which might impair the ability to participate inthis study to the full extent, or which may require treatment that could interactwith study treatment. Evidence of untreated urinary tract obstruction (e.g.,hydroureter or hydronephrosis). Participants who undergo a successful decompressiveprocedure prior to treatment and participants with chronic, stable mild to moderatehydronephrosis without renal impairment will not be excluded.

• Has a known alteration in breast cancer genes (BRCA) BRCA1 or BRCA2 and are eligibleto receive poly ADP ribose polymerase (PARP) inhibitor therapy according to theirtreating institution's standard of care. Note, participants with BRCA mutations whohad disease progression on PARP inhibitors or who are not eligible for treatmentwith PARP inhibitors, are eligible.

• Has severe claustrophobia or other condition (e.g., pain) that may impact theability to comply with the imaging aspects of this protocol.