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

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• Prostatic Neoplasms 6,370

Prostatic Neoplasms

6,370 studies on the registry are indexed under Prostatic Neoplasms; 1,399 are open to participants now.

This study's planned enrollment of 100 is above the median of 58 across 4,822 interventional studies indexed under Prostatic Neoplasms.

Lead sponsor

This is the only study on the registry with AdvanCell Pty Limited as lead sponsor.

Eligibility criteria

Study arms

• Experimental
  Phase 1b

  Phase 1b Dose Escalation: Participants with PSMA-positive mCRPC who have had exposure to at least one ARPi and taxane-based chemotherapy (unless taxanes contraindicated or declined) at any time in the course of their disease.

  Drug: [²¹²Pb]Pb-ADVC001 (Phase 1b)

• Experimental
  Phase 2a

  Group 1: Participants with PSMA-positive mHSPC with PSA ≥ 0.2 ng/mL despite androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPi) without evidence of disease progression Group 2: Participants with PSMA-positive mCRPC who have 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. Group 3: Participants with PSMA-positive mCRPC who have had exposure to at least one ARPi and to 177Lu-PSMA at any time in the course of their disease.

  Drug: [²¹²Pb]Pb-ADVC001 (Phase 2a)

Interventions

• Drug[²¹²Pb]Pb-ADVC001 (Phase 1b)

  Ph1b 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

• Drug[²¹²Pb]Pb-ADVC001 (Phase 2a)

  Ph2a 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.

Primary outcomes

1. 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.

   Time frame: Up to 60 Months

2. 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.

   Time frame: Up to 60 months

3. 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.

   Time frame: Up to 60 months

4. 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.

   Time frame: Up to 60 months

5. Therapeutic efficacy as assessed by progression-free survival (Phase 1b/2a)

   Progression-free survival defined as the time from date of first dosing to the occurrence of one of the following: 1. Radiographic progression per RECIST 1.1 or bone scan in accordance with PCWG3 criteria. 2. Clinical progression as determined by investigator assessment. 3. PSA progression defined by PCWG3. 4. Death due to any cause.

   Time frame: Up to 60 months

6. Therapeutic efficacy as assessed by overall survival (Phase 1b/2a)

   Overall survival defined as the time from date of first dosing to death from any cause.

   Time frame: Up to 60 months

Secondary outcomes

1. 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.

   Time frame: Up to 60 months

2. 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.

   Time frame: Up to 60 months

3. Dosimetry (Phase 1b/2a)

   Absorbed radiation doses (expressed as Gy/MBq) of administered \[²¹²Pb\]Pb-ADVC001 to organs at risk and tumor lesions.

   Time frame: Day 1 of the first cycle through to the end of treatment (28 days after administration of the last treatment cycle).

4. 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

   Time frame: Up to 60 months

Other outcomes

1. 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.

   Time frame: Up to 24 weeks

2. 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.

   Time frame: Up to 24 weeks

3. Biomarkers of immune activation (Phase 1b/2a)

   Change from baseline in biomarkers of immune activation and efficacy endpoints including PSA response and ORR.

   Time frame: Up to 32 weeks

4. PK parameter: Maximum observed concentration (Cₘₐₓ) of [²¹²Pb]Pb-ADVC001 in blood (Phase 1b/2a)

   Time frame: On the first and second day of study treatment

5. PK parameter: Time to maximum observed concentration (Tₘₐₓ) of [²¹²Pb]Pb-ADVC001 in blood (Phase 1b/2a)

   Time frame: On the first and second day of study treatment

6. PK parameter: Area under the concentration-time curve (AUC) of [²¹²Pb]Pb-ADVC001 in blood (Phase 1b/2a)

   Time frame: On the first and second day of study treatment

7. PK parameter: Clearance of [²¹²Pb]Pb-ADVC001 in blood (Phase 1b/2a)

   Time frame: On the first and second day of study treatment

8. PK parameter: Amount of [212Pb]Pb-ADVC001 eliminated in urine (Phase 1b/2a)

   Time frame: On the first and second day of study treatment

9. PK parameter: [212Pb]Pb-ADVC001 metabolites in urine (Phase 1b/2a)

   Time frame: On the first and second day of study treatment

10. Exploratory [212Pb]Pb PET/CT imaging (Phase 1b/2a)

    Biodistribution of \[212Pb\]Pb-ADVC001 via \[212Pb\]Pb PET/CT.

    Time frame: Up to 5 weeks

Individual participant data

Plan to share: No