Targeted Alpha Therapy With 225Actinium-PSMA-I&T of Castration-resISTant Prostate Cancer (TATCIST).

Study Overview
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Brief Summary
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The treatment regimen will consist of 4 doses of 225Ac-PSMA-I&T

Detailed Description
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The treatment regimen will consist of 4 doses of 225Ac-PSMA-I&T, administered at 8 ± 1 week intervals, with an initial activity of 100 kBq/kg (±10%). Additional doses will be administered at 100 kBq/kg (±10%) with the following exceptions: Patients who experience dose-modifying events should be managed as outlined in Table 6. Patients with a confirmed decline in PSA ≥ 50% (2 consecutive measurements at least 3 weeks apart) should have their dose of 225Ac-PSMA-I&T de-escalated to 87 kBq/kg(±10%). Additional de-escalations to 75 kBq/kg (±10%) then 50 kBq/kg (±10%) will be taken if PSA continues to decline > 85%. 225Ac-PSMA-I&T will be administered as an intravenous (I.V.) infusion over approximately 1-3 minutes.

Official Title
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PSMA-directed Targeted Alpha Therapy With 225Ac-PSMA-I&T of Castration-resISTant Prostate Cancer (TATCIST). A Phase II Clinical Trial.

Conditions
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Metastatic Castration Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Ac225-PSMA I&T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have the ability to understand and sign an approved informed consent (ICF). Patients must have the ability to understand and comply with all protocol requirements. Adenocarcinoma of Prostate proven by histopathology. Life expectancy of 6 months or more. Unresectable metastases. Progressive disease, with docetaxel/cabazitaxel or declined taxane therapy by the patient. If known BRCA mutations or microsatellite instability is present, patients should have received FDA approved therapies such as PARP inhibitors and pembrolizumab, and progressed Castration resistant disease with confirmed testosterone level ≤50 ng/dL under prior androgen deprivation therapy (ADT) Positive 68Ga-PSMA-11 PET/CT (or equivalent PSMA-ligand PET/CT) for the majority of measurable disease defined as SUV ≥2.0, including bone-only metastatic disease. ECOG 0-1. Hemoglobin concentration ≥ 9.0 g/dL. Platelet counts ≥100 × 109/L. White blood cell count ≥ 2.0 × 109/L), ANC>1.5 x109/L Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =<3.0 x ULN Billirubin ≤ 3x ULN. Albumin ≥ 2.5 g/dL. Serum/plasma creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula Received at least one ARAT in the past. Patients on anti-androgen therapy are allowed to continue their treatment at the descretion of their oncologists. Exclusion Criteria: Less than 6 weeks since last myelosuppressive therapy (including Docetaxel, Cabazitaxel, 223Ra, 153Sm, 177Lu-PSMA-617/other Lu-PSMA RLT ) or other radionuclide therapy permitted (including 223Ra, 153Sm). Patients who received previous treatment with Actinium-225 are excluded. Urinary tract obstruction as evidenced by Tc-99m DTPA renal scan with diuretics. Abnormal renal function (eGFR <60 mL/min), baseline Hgb <9g/dL, ANC<1.5 x109/L, platelets <100 x109/L, and PT, INR or PTT ≥1.5xULN Persistent baseline dry eye or dry mouth from prior RLT. Persistent prior AEs >Grade 1 from prior anti-cancer therapies. Administration of an investigational agent ≤60 days or 5 half-lives, whichever is shorter, prior to C1W0. Known presence of central nervous system metastases or liver metastases. Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer. Concurrent illness that may jeopardize the patient's ability to undergo study procedures. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cordcompression. Concurrent serious (as determined by the investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure (see 12.1Appendix 1), unstable ischemia, uncontrolled symptomatic arrhythmia, 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. Major surgery ≤30 days prior to randomization. Planning to conceive pregnancy during the treatment and up to 6 months after the last treatment.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ac225-PSMA I&T<br>All patients will receive 225Ac-PSMA-I&T, administered at 8 ± 1-week interval, with the initial activity of 100 kBq/kg (±10%), then de-escalation to 87 kBq/kg (±10%), 75 kBq/kg (±10%) or 50 kBq/kg (±10%) in cases of good response (PSA decline >50%), at the discretion of the principal investigator. | Drug: Ac225-PSMA I&T<br>* Peptide capable of binding to the domain of PSMA radiolabeled with Ac225<br>* Other names: Ac225-PSMA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the efficacy after 225Ac-PSMA-I&T in patients with metastatic castration-resistant prostate cancer with RLT refractory or without prior 177 Lu-PSMA-617. | The efficacy is defined by measurement of PSA level and more than 50% decline after 225Ac-PSMA-I&T. MRI scans of the abdomen and pelvis with and without contrast, CT of the chest with contrast only, and bone scan will be performed at baseline, before each treatment, and every 3 months after last treatment until the last follow up. | 24 months after last dose administration | 
| Determination of the safety after 225Ac-PSMA-I&T by measuring changes in the level of alkaline phosphatase (ALT) in patients with prostate cancer | Safety measured by determination of notable changes in Alkaline phosphatase (ALP) levels ([ULN] done before therapy and every week for the first 8 weeks after the first treatment and every 2 weeks during the rest of the treatments and every month after the last treatment until completion of follow-up or patient progression. | 24 months after last dose administration | 
| Determination of the safety after 225Ac-PSMA-I&T by measuring changes in the level of alkaline transferase (AST) in patients with prostate cancer | Safety measured by determination of notable changes in Alkaline transferase (AST) levels ([ULN] done before therapy and every week for the first 8 weeks after the first treatment and every 2 weeks during the rest of the treatments and every month after the last treatment until completion of follow-up or patient progression. | 24 months after last dose administration | 
| Determination of the safety after 225Ac-PSMA-I&T by measuring changes in the level of creatinine clearance in patients with prostate cancer | Safety measured by determination of the notable changes in creatinine clearance [mL/min] done before therapy and every week for the first 8 weeks after the first treatment and every 2 weeks during the rest of the treatments and every month after the last treatment until completion of follow-up or patient progression. | 24 months after last dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the maximum PSA decline after all cycles of therapy with 225Ac-PSMA-I&T. | The PSA [ng/ml] level will be measured at baseline after all cycles of treatment | 24 months after last dose administration | 
| Determination of PSA progression-free survival (PFS) | Progression -free survival will be measured in months from start of therapy until death or PSA progression. | 24 months after last dose administration | 
| Determination of duration of response | It will be measured from the first date of complete response or partial response based on RECIST 1.1/PCWG3 criteria or death in the absence of progression | 24 months after last dose administration |