[Ac-225]-PSMA-62 Trial in Oligometastatic Hormone Sensitive and Metastatic Castration Resistant Prostate Cancer

[Ac-225]-PSMA-62 Phase I/II Clinical Trial to Characterize Efficacy, Safety, Tolerability, and Dosimetry in Oligometastatic Hormone Sensitive and Metastatic Castration Resistant Prostate Cancer (ACCEL)

ACCEL is a multicenter, open label phase Ia/Ib/II study of [Ac-225]-PSMA-62 in participants with prostate-specific membrane antigen (PSMA)-positive prostate cancer.

The primary aim of the phase Ia study is to evaluate the safety and tolerability of [Ac-225]-PSMA-62 to determine the maximum tolerated dose (MTD). The primary aim of the randomized phase Ib dose optimization is to determine the recommended phase II doses (RP2D) for patients with mCRPC and OmHSPC. The aim of the phase II study for patients with mCRPC is to evaluate the efficacy of [Ac-225]-PSMA-62.

Inclusion Criteria:

1. Histological, pathological, and/or cytological confirmation of adenocarcinoma of the prostate

2. ECOG performance status 0 to 1

3. Criteria specific for patients with mCRPC:

   1. Previously received an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy (unless ineligible or refused taxane). Received a maximum of 3 prior systemic therapy regimens in the mCRPC setting

   2. Progressive mCRPC at the time of consent based on at least 1 of the following criteria being met in the context of castrate levels of testosterone:

      • PSA progression defined as rising PSA values at a minimum of 1-week intervals, with the last result being at least 1.0 ng/mL
      • Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions
      • Progression of bone disease defined as the appearance of two or more new lesions by bone scan

   3. At least one PSMA-PET positive lesion for prostate cancer

   4. Castrate circulating testosterone levels (<1.74 nmol/L or <50 ng/dL)

4. Criteria specific for patients with OmHSPC:

   1. PSA recurrence after radical prostatectomy (RP) or definitive radiation therapy (RT), with or without adjuvant/salvage local therapy (radiation or surgery), with or without (neo)adjuvant ADT

      • PSA ≥ 0.2ng/mL for patients with prior RP +/- RT, or
      • PSA of ≥ 2 ng/mL above nadir for patients with only prior RT

   2. 1- 5 PSMA-PET positive lesions identified outside the prostate bed or remaining gland.

Exclusion Criteria:

1. Patient has received any other investigational therapeutic agents within 4 weeks or 5 half-lives (whichever is shorter) of starting the study treatment

2. Evidence of ongoing and untreated urinary tract obstruction

3. Existing Grade 1 dry mouth (xerostomia) or symptomatic Grade 1 dry eye (xerophthalmia) for any reason

4. Patient has any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while on the study or that could confound discrimination between disease- and study treatment-related toxicities

5. Criteria specific for patients with mCRPC:

   1. Patient has received any PSMA-directed radioligand therapy (e.g., Lu-177-PSMA, Lu-177-PNT2002, Ac-225-J591)
   2. Patient has received any therapeutic systemic radionuclides (e.g., radium-223, rhenium-186, strontium-89), or non-PSMA-directed therapeutic radioligands (e.g., Lu-177-Dotatate) within 5 half-lives of starting the study treatment

6. Criteria specific for patients with OmHSPC:

   1. Patient has received any systemic anti-cancer therapy for prostate cancer with the exception of (neo)adjuvant ADT for management of localized disease
   2. Presence of any liver metastases
   3. Known presence of central nervous system metastases