Dose Escalation and Efficacy Study of 212Pb-ADVC001 in Patients With Metastatic Castration Resistant Prostate Cancer.

Study Overview
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Brief Summary
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This is a first-in-human, dose escalation and efficacy study of [212Pb]Pb-ADVC001 in participants with PSMA-positive metastatic Castration Resistant Prostate Cancer (mCRPC).

Detailed Description
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This is a single arm, non-randomized, toxicity and dose finding study. The trial will include a maximum of 18 patients with confirmed mCRPC and no prior history of radioligand therapy. The study is based on a 3 + 3 design with 4 cohorts of patients receiving escalating doses 60, 90, 120 and 150MBq of [212Pb]Pb-ADVC001. Each patient in each cohort will be given the same dose and a maximum of 4 cycles of therapy administered at 6 weekly intervals. The decision to recruit the next cohort of patients and escalate the dose will be made after reviewing all safety data from the previous cohort acquired over 6 weeks after the first cycle of therapy. In this manner, recruitment of the next cohort can occur before all treatment cycles have been administered to the previous cohort.

Official Title
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TheraPb: Phase I/IIa Dose Escalation and Toxicity Study of [212Pb]Pb-ADVC001 in Metastatic Prostate Adenocarcinoma

Conditions
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Prostatic Neoplasms, Castration-Resistant

Intervention / Treatment
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* Drug: [212Pb]Pb-ADVC001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and 18 years of age or older at the time of signing the consent form with metastatic adenocarcinoma of the prostate, confirmed by histopathology. Castration-resistant prostate cancer progressing or has progressed on androgen receptor therapy. Had exposure to a taxane-based chemotherapy at any time in the course of their disease, unless contraindicated or declined. • Progressive disease with rising PSA level, or new lesion(s) in the viscera or lymph nodes as per RECIST 1.1 or in bone as per Prostate Cancer Working Group 3. Significant PSMA avidity on 68Ga-PSMA PET/CT or 18F-based PSMA PET/CT (at least one site of disease with maximum standardised uptake value (SUVmax) ≥ 1.5 times the SUV of normal liver). Eastern Cooperative Oncology Group (ECOG) Performance status 0 to 2. Adequate renal, bone and liver function (Absolute neutrophil count: ≥2 x 10^9/L , Hemoglobin: ≥90 g/L, Platelet count: >150,000 x 10^9/L, Serum creatinine: <1.5 x upper limit of normal (ULN) i.e ≤ 125 umol/L or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault formula, Serum total bilirubin: <1.5 x ULN (unless the patient has Gilbert's syndrome in which case direct bilirubin must be normal), Serum aspartate aminotransferase (AST) and alanine transaminase (ALT): <1.5 x ULN in the absence of liver metastases; <3 x ULN if due to liver metastases (in both circumstances bilirubin must meet entry criteria). Estimated life expectancy >12 weeks Willing and able to comply with all study requirements, including the timing and nature of all required assessments. Agree to practice adequate precautions to prevent pregnancy in a partner. Exclusion Criteria: Prostate cancer with known significant sarcomatoid or spindle cell or neuroendocrine small cell components. Sjogren's syndrome or other pathologies affecting salivary gland function. Prior treatment with radiopharmaceuticals containing the following radioisotopes: lutetium-177, actinium-225, strontium-89, samarium-153, rhenium-186, rhenium-188, radium-223 or other lead-212-containing radiopharmaceuticals. Received systemic anti-cancer therapy and/or radiation therapy within four weeks of Screening. Received any investigational agent within four weeks of Screening. Contraindications to the use of corticosteroid treatment. Concurrent other malignancies that are expected to alter life expectancy or may interfere with disease assessment. Known brain metastases of any size or hepatic metastases > 1 cm (longest diameter). Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety. 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. Severe claustrophobia that may impact the participants ability to comply with all aspects of the imaging protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: This is a single arm, non-randomized study based on a 3 + 3 design modified to incorporate measures of both toxicity and tumour response. A minimum of 3 participants will be treated at each dose level and evaluated for dose limiting toxicity for 6 weeks before consideration is made to enroll the next cohort of participants and dose escalate. Four dose levels will be considered, namely 60 MBq, 90 MBq, 120 MBq and 150 MBq of [212Pb]Pb-ADVC001. Up to 4 cycles of [212Pb]Pb-ADVC001 will be administered at 6 weekly intervals. Dose levels can be de-escalated across subsequent cycles to manage any toxicity if participants show tumour response.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: [212Pb]Pb-ADVC001<br>There is only a single treatment arm. Participants with metastatic Castration Resistant Prostate Cancer that have received prior Androgen Receptor Pathway Inhibitors (e.g., Abiraterone, Enzalutamide) and chemotherapy (or can have declined chemotherapy), who have not been previously treated with [177Lu]Lu-PSMA radioligand therapy. Four cohorts will receive escalating doses of 60 MBq, 90 MBq, 120MBq and 150MBq of [212Pb]Pb-ADVC001. Participants will receive a dose via intravenous injection every 6 weeks (+/- 2 weeks) for no more than 4 cycles. | Drug: [212Pb]Pb-ADVC001<br>* [212Pb]Pb-ADVC001 administered intravenously under the dose escalation schedule<br>* Other names: 212Pb-ADVC001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), assessed in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. |  | Up to Week 36 | 
| Incidence and severity of dose-limiting toxicities, assessed in accordance with NCI CTCAE V5. |  | Up to Week 6 | 
| Frequency of clinically significant changes from baseline in clinical chemistry and hematology laboratory values. |  | Up to Week 36 | 
| Maximum tolerated dose (MTD) of [212Pb]Pb-ADVC001, assessed using the standard 3+3 dose escalation design. |  | Up to 6 weeks | 
| Recommended Phase 2 Dose (RP2D) for [212Pb]Pb-ADVC001. | The RP2D is defined as the dose level that is well tolerated in patients. This will be equal or less than the MTD. In the case where an MTD is not identified, even at the highest dose level tested, the RP2D may be determined based on data indicating adequate tolerability and therapeutic effectiveness. | Through study completion, estimated 12 months study duration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole body biodistribution and organ radiation dosimetry of [212Pb]Pb-ADVC001 | Absorbed radiation doses to kidneys, liver, lungs, spleen, and salivary glands. | Up to Week 19 | 
| Whole body biodistribution and organ radiation dosimetry of [212Pb]Pb-ADVC001 | Favourable and selective uptake of [212Pb]Pb-ADVC001 in PSMA-expressing tumours as determined by qualitative image read by expert radiologist or nuclear medicine physician, and, where possible, tumour-to-healthy tissue ratios. | Up to Week 19 | 
| Comparability of biodistribution of [212Pb]Pb-ADVC001 to PSMA targeting positron emission tomography (PET) imaging agents | Biodistribution of [212Pb]Pb-ADVC001 and 68Ga-PSMA (or 18F based-PSMA), as determined by image interpretation by expert radiologist or nuclear medicine physician. | Up to Week 19 | 
| Radiographic progression free survival (rPFS) | rPFS defined as the time from enrolment to the occurrence of one of the following: Progression of measurable lesions using RECIST 1.1; Progression of bone lesions using PCWG3 criteria; Death due to any cause; | Up to Week 25 | 
| Objective response rate | Objective response rate in patients with measurable disease (RECIST 1.1). | Up to Week 25 | 
| Prostate specific antigen (PSA) response | PSA response defined as a reduction from baseline PSA level of at least 50%, maintained for at least 3 weeks. | Up to Week 36 | 
| Change from baseline in serum alkaline phosphatase (ALP) values. |  | Up to Week 36 |