This is a prospective, open-label, dose-escalation and randomized dose optimization and expansion study. The Phase Ib portion of the study aims to determine the safety and tolerability of escalating doses of \[212Pb\]Pb-ADVC001 administered every 6, 4, 2 or 1 week(s) and establish the recommended phase 2 doses (RP2D). The Phase 2a expansion aims to assess the efficacy and safety of \[212Pb\]Pb-ADVC001 at the RP2 doses in 3 participant groups.
Documented metastatic adenocarcinoma of the prostate, confirmed by histopathology.
Increase in PSA greater than 25% and > 2 ng/mL above nadir, confirmed by progression at two timepoints at least three weeks apart
Progressive disease or new lesion(s) (relative to previous imaging) in the viscera or lymph nodes as per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or in bone as per Prostate Cancer Clinical Trials Working Group 3 (PCWG3).
For Phase 1b Dose Escalation: Metastatic castration-resistant prostate cancer (mCRPC) with 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 as documented in the patient's source documents and eCRF).
Has received prior systemic radioligand therapy with the exception of prior radium-223. Prior 177Lu-PSMA is required for Phase 2a Group 3 participants.
Systemic anti-cancer therapy and/or radiation therapy within four weeks of C1D1 or has received any investigational agent within four weeks of C1D1.
Has malignancies other than prostate cancer within 3 years prior to enrolment, except for those with a negligible risk of metastases
Known CNS metastases or symptoms of spinal cord compression or impending spinal cord compression. Patients with prior treatment for spinal cord compression should be clinically stable off steroids for at least 4 weeks.
Parallel
[²¹²Pb]Pb-ADVC001 (Phase 1b)
DrugPh1b Escalation Drug: \[²¹²Pb\]Pb-ADVC001administered intravenously per dose escalation scheme Dose Level 1 \- 60 MBq, 4 cycles every 6 weeks Dose Level 2a \- 120 MBq, 4 to 6 cycles every 4 weeks Dose Level 2b \- Optional cohort of 120 MBq, 4 to 6 cycles every 2 weeks Dose Level 3a \- 160 MBq, 4 to 6 cycles every 4 weeks Dose Level 3b \- Optional cohort of 160 MBq, 4 to 6 cycles every 2 weeks Dose Level 3c \- Optional cohort of 160 MBq, 4 to 6 cycles every week Dose Level 4a * 200 MBq, 4 to 6 cycles every 4 weeks Dose Level 4b \- Optional cohort of 200 MBq, 4 to 6 cycles every 2 weeks Dose Level 4c \- Optional cohort of 200MBq, 4 to 6 cycles every week
[²¹²Pb]Pb-ADVC001 (Phase 2a)
DrugPh2a Expansion Drug: All participants are randomized 1:1 to receive either 160 or 200 MBq of ADVC001. Each participant receives up to 12 doses according to an adaptive dosing schedule and rules allowing for a treatment pause ('treatment holiday') with the possibility of subsequent therapy restarts. All participants continue ADT throughout the study. Group 1 participants receive ongoing ARPi as per standard of care, and Group 2 participants also are randomized to receive ADVC001 ± concomitant ARPi.
RP2D (Phase 1b)
Incidence and severity of dose-limiting toxicities, as defined in Section 6.5 of the protocol and assessed in accordance with NCI CTCAE Version 5.0. Incidence and severity of adverse events, SAEs and radiation adverse events of special interest, assessed in accordance with NCI CTCAE Version 5.0.
Therapeutic efficacy as assessed by PSA response (Phase 1b/2a)
PSA response defined as a reduction from baseline PSA level of at least 50% (PSA 50) and 90% (PSA 90), confirmed by a follow-up PSA.
Therapeutic efficacy as assessed by objective response rate and disease control rate (Phase 1b/2a)
Objective response rate (OCR) and disease control rate (DCR) derived from CT imaging based on RECIST 1.1 and Prostate Cancer Trials Working Group 3.
Therapeutic efficacy as assessed by radiographic progression-free survival (Phase 1b/2a)
Radiographic progression-free survival (rPFS) defined as the time from date of first dosing to the occurrence of one of the following: 1. Progression of measurable lesions using RECIST 1.1. 2. Progression of bone lesions using Prostate Cancer Working Group 3 criteria. 3. Death due to any cause.
Maximum tolerated dose (MTD) (Phase 1b)
Incidence and severity of dose-limiting toxicities, as defined in Section 6.5 of the protocol and assessed in accordance with NCI CTCAE Version 5.0.
Safety and Tolerability (Phase 1b/2a)
Incidence and severity of adverse events, SAEs and radiation adverse events of special interest, assessed in accordance with NCI CTCAE Version 5.0.
Dosimetry (Phase 1b/2a)
Absorbed radiation doses (expressed as Gy/MBq) of administered \[²¹²Pb\]Pb-ADVC001 to organs at risk and tumor lesions.
Time to next non-study anti-cancer treatment from completion of [²¹²Pb]Pb-ADVC001 treatment (Phase 2a)
Median time to commencement of next (non-study) anti-cancer treatment following completion of \[²¹²Pb\]Pb-ADVC001 treatment
Biodistribution (Phase 1b/2a)
Biodistribution of \[²¹²Pb\]Pb-ADVC001 on SPECT/CT and \[⁶⁸Ga\]Ga-PSMA (or \[¹⁸F\]F-based-PSMA) on PET/CT as determined by image analysis and interpretation by expert readers.
PSMA PET response (Phase 1b/2a)
\[⁶⁸Ga\]Ga- or \[¹⁸F\]F-based PSMA responses based on the Consensus Statement on PSMA PET Response Assessment Criteria in Prostate Cancer.
Biomarkers of immune activation (Phase 1b/2a)
Change from baseline in biomarkers of immune activation and efficacy endpoints including PSA response and ORR.
PK parameter: Maximum observed concentration (Cₘₐₓ) of [²¹²Pb]Pb-ADVC001 in blood (Phase 1b/2a)
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