Comparing Lutetium-177 and Actinium-225 PSMA-targeted radiation before prostatectomy

Comparison of 177Lu-PSMA-617 and 225Ac-PSMA-617 in a Prostatectomy Model (LUTACT Trial)

This will test whether giving one of two PSMA-targeted radiation drugs (Lutetium-177 or Actinium-225) before prostate removal works differently in men with high or very high-risk localized prostate cancer.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 45 (estimated)
• Ages: 18 Years and up
• Sex: Male
• Sponsor: University of California, San Francisco (Academic / other)
• Drugs / interventions: radiation
• Locations: 1 site (San Francisco, California)
• Trial ID: NCT07054346 on ClinicalTrials.gov

What this trial studies

This single-center, Phase 1 pilot compares two PSMA-directed radioligand therapies given as neoadjuvant treatment to men with high or very high-risk localized or locoregional prostate cancer who plan to undergo radical prostatectomy. Participants receive either 177Lu-PSMA-617 or 225Ac-PSMA-617 with imaging (PSMA PET, SPECT/CT) and tissue collection at prostatectomy to measure tumor absorbed dose, cell necrosis, and immune effects. The study will also track safety, PSA changes, and pathologic response, and will perform mRNA profiling to explore biological differences between treatments. Findings are intended to inform dosing, mechanisms of action, and design of future larger trials.

Who should consider this trial

Good fit: Adult men with histologically confirmed high or very high-risk localized or locoregional prostate adenocarcinoma who are candidates for radical prostatectomy, have no distant metastases on PSMA PET, a primary tumor >1.5 cm on MRI, and PSMA PET SUVmax >10 are the intended participants.

Not a fit: Patients with distant metastatic disease, low PSMA uptake (SUVmax ≤10), very small primary tumors (<1.5 cm), or who are not surgical candidates are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, the study could identify which PSMA radioligand provides greater tumor kill or immune priming before surgery, guiding better preoperative treatment choices.

How similar studies have performed: PSMA-targeted Lutetium-177 and small series of Actinium-225 have shown promising activity in advanced metastatic prostate cancer, but using these agents as neoadjuvant therapy before prostatectomy is exploratory and not yet established.

Eligibility criteria

Inclusion Criteria:

1. Histologically confirmed prostate adenocarcinoma.
2. Willing to undergo prostatectomy with or without lymph node dissection, and candidate for prostatectomy as determined by urologic oncology.
3. High-risk disease as defined as meeting 1 or more of the 3 following criteria:

   1. Gleason score of 4+5 disease or higher.
   2. Pelvic nodal metastases on PSMA PET.
   3. Extracapsular extension or seminal vesicle invasion on MRI.
4. No evidence of distant metastatic disease as determined by PSMA PET. Nodal disease below the iliac bifurcation (clinical stage N1) is allowed.
5. Maximum Standardized Uptake Value (SUVmax) in the primary tumor greater than 10 on PSMA PET using Gallium-68 (68Ga)-PSMA-11 or piflufolastat F 18 (18F-DCFPyL).
6. Target tumor in the prostate measuring greater than 1.5 cm on MRI.
7. Age ≥18 years.
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%),
9. Demonstrates adequate organ function as defined below:

   1. Platelets ≥100,000/mcL, independent of transfusions or growth factors within 3 months of treatment start.
   2. Hemoglobin ≥10 g/dL, independent of transfusions or growth factors within 3 months of treatment start.
   3. Absolute Neutrophil Count (ANC) ≥1,500/microliter (mcL).
   4. Creatinine clearance Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2 , calculated using the Cockcroft-Gault equation.
   5. Albumin ≥2.5 g/dL.
   6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN.
   7. Total bilirubin (TBIL) ≤2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤3 x ULN is permitted.
10. Ability to understand and the willingness to sign a written informed consent document.
11. Participants must provide consent to comply to recommended radioprotection precautions during study.
12. Participants must use adequate contraception and not donate sperm while on study drug and for at least 14 weeks after the last study treatment.

Exclusion Criteria:

1. Has received prior prostate cancer therapy.

   a. Prior 5-alpha reductase inhibitors (e.g. finasteride, dutasteride) allowed if discontinued at least 3 weeks prior to treatment start.
2. Has participated in a study of an investigational therapeutic product and received study treatment or used an investigational device within four weeks of the first dose of treatment.
3. Dry mouth that impacts the eating of food (i. e. requiring mouthwash prior to eating).
4. Concurrent serious (as determined by the principal investigator) medical conditions including but not limited to New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.
5. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease free, treatment free for more than 3 years prior to randomization, or participants with adequately treated non-melanoma skin cancer, superficial bladder cancer are eligible.
6. Individuals with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
7. Prior external beam radiation therapy (EBRT) to the prostate or prostate bed.

Additional exclusion criteria applicable only to participants undergoing intraarterial administration of PSMA RLT:

1. Severe allergy to iodinated contrast.
2. Severe atherosclerosis from prior CT imaging study, or greater than 10 pack-year smoking history if no prior imaging available.

Where this trial is running

San Francisco, California

• University of California, San Francisco — San Francisco, California, United States (Recruiting)

Study contacts

• Principal investigator: Thomas A Hope, MD — University of California, San Francisco
• Study coordinator: Maya Aslam

Conditions Prostate Cancer; High-risk Prostate Cancer; Localized Prostate Carcinoma; Very High Risk Prostate Carcinoma; Radioligand Therapy