Study With [225Ac]Ac-FL-020 in mCRPC Participants

A Phase 1, First-in-Human, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of [225Ac]Ac-FL-020 in Participants With mCRPC.

The purpose of this study is to evaluate the safety, therapeutic effect, and pharmacokinetics of [225Ac]Ac-FL-020 in participants with metastatic castration-resistant prostate cancer (mCRPC).

The aim of this Phase 1, First-in-Human, Open-label Trial is to evaluate the safety, tolerability, pharmacokinetics, and efficacy of [225Ac]Ac-FL-020 as a single agent in participants with metastatic Castration-Resistant Prostate Cancer (mCRPC). [111In]In-FL-020 serves as a surrogate for 225Ac-FL-020 for dosimetry purposes. The trial is divided into two parts: dose escalation in Part 1 and cohort expansion in Part 2.

Inclusion Criteria:

1. Histologically or cytologically confirmed metastatic CRPC.

2. Age ≥ 18 years.

3. Signed informed consent, and able and willing to comply with protocol requirements prior to any study procedures.

4. Patients must have a life expectancy >3 months.

5. All patients are required to have one or more positive lesions detected by PSMA-PET/CT scan

6. Documented progression of the disease based on the Investigator judgement

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

8. Have a castrate serum testosterone < 50 ng/dL or <1.7 nmol/L. Patients must continue primary androgen deprivation with an LHRH analogue (agonist/antagonist) if they have not undergone bilateral orchiectomy.

9. Have previously been treated with at least one of the following:

   1. Androgen receptor signaling inhibitor (such as enzalutamide).
   2. CYP 17 inhibitor (such as abiraterone acetate).

10. Patients must have been previously treated with at least 1, but no more than 2 previous taxane regimens. Note: In cases where patients are unwilling to undergo taxane therapy due to concerns regarding its potential toxicity, enrollment of patients previously not treated with taxane might be considered after careful evaluation by the investigator. In such cases, patients will be fully informed about the potential benefits of taxane therapy, including its role in prolonging survival.

11. Adequate organ function as defined by:

    1. Absolute neutrophil count (ANC) ≥2 x 10^9/L (2000/µL),
    2. Hemoglobin ≥9.0 g/dL,
    3. Platelets ≥90 x 10^9/L (90 000/µL),
    4. Serum albumin >3g/dL
    5. Aspartate aminotransferase (AST) ≤2.5 x ULN; alanine aminotransferase (ALT) ≤2.5 x ULN (AST, ALT ≤5 x ULN if liver metastases are present),
    6. Serum total bilirubin ≤1.5 x ULN (≤5 x ULN if liver metastases present)
    7. Creatinine clearance ≥60 mL/min calculated using a standard Cockcroft and Gault formula.
    8. Q wave to T wave (QT) interval corrected for heart rate (QTc) <470 ms

Exclusion Criteria:

1. Patients with known brain metastases.
2. Grade 3 Cystitis infective and non-infective.
3. Severe acute or chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with the study participation or the study treatment administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for enrollment in this study.
4. More than 1 prior treatment with PSMA-targeted radioconjugate.
5. Previous treatment with Actinium-225, Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, or hemi-body irradiation or any other radionuclide therapy except [177Lu]Lu-PSMA-617 and Radium-223.
6. Radium-223 within 6 months prior to the first study treatment administration.
7. Prior radioconjugate treatment within 6 weeks prior to first study treatment administration. Adverse events from prior radioconjugate treatment must be resolved or reduced to grade 1 prior to the first study treatment administration.
8. More than 6 administrations of previous radioconjugate treatment.
9. Any systemic anti-cancer therapy (e.g., chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies]) within 6 weeks prior to the first study treatment administration. Patients on a stable bisphosphonate or denosumab regimen for 30 days prior to first study treatment administration are eligible.
10. Evidence of superscan in the baseline bone scan.
11. Any investigational agents within 6 weeks prior to the first study treatment administration.
12. Radiotherapy: external beam radiotherapy that encompasses >30% of bone marrow completed less than 6 weeks or focal radiation completed less than 2 weeks, prior to the first study treatment administration.
13. Major surgery (not including placement of vascular access device or tumor biopsies) within 6 weeks prior to first dose of the study treatment, or no recovery from side effects of such intervention.
14. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
15. Known hypersensitivity to the components of the study therapy or its analogs.
16. Enrollment in another interventional clinical study.
17. Any persistent xerostomia or dry eyes from previous treatment
18. Persistent prior AEs > Grade 1 from prior anti-cancer therapies.
19. Significant cardiac disease, such as recent (within six months prior to first dose of the study treatment) myocardial infarction or acute coronary syndromes (including unstable angina pectoris), congestive heart failure (New York Heart Association class III or IV), uncontrolled hypertension, uncontrolled cardiac arrhythmias, severe aortic stenosis.
20. History of thromboembolic or cerebrovascular events, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, or pulmonary emboli within 6 months prior to first dose of the study treatment.
21. Known active infection requiring therapy, including known active infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or SARS-CoV-2
22. Prior history of malignancy other than inclusion diagnosis within three years prior to first dose of the study treatment
23. Known history of myelodysplastic syndrome.