Actium-225-Prostate Specific Membrane Antigen Imaging & Therapy

Study Overview
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Brief Summary
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225Ac-PSMA I&T is a radiopharmaceutical for therapy of prostate cancer. PSMA is overexpressed on prostate cancer cells. Actium-225 is an alpha emitting radionuclide. When PSMA I&T is labelled with Actium-225, it can be applied as therapy for prostate cancer.

Detailed Description
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Rationale: 225Ac-PSMA I&T is a radiopharmaceutical for therapy of prostate cancer. PSMA is overexpressed on prostate cancer cells. Actium-225 is an alpha emitting radionuclide. When PSMA I&T is labelled with Actium-225, it can be applied as therapy for prostate cancer. Objective: To evaluate the tolerability and safety of 225Ac-PSMA I&T in patients with metastatic prostate cancer and recommend a dose for further phase 2 studies. Study design: A clinical prospective, single-center, single-arm, phase I dose escalation therapy study. Study population: Up to 30 patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Intervention: Patients with advanced mCRPC will receive therapy with 225Ac-PSMA I&T. The first dose-level will not exceed 8 megabecquerel (MBq), as this is reported in the literature as a save activity for treatment. A Positron Emission Tomography - Magnetic Resonance Imaging (PET-MRI) with Gallium-68-PSMA I&T (68Ga) will be performed to calculate the precise dose-level needed and as a verification the precise dose-level will be compared with the dose-level of 8 MBq. In the first week after therapy, the PET-MRI will be repeated to observe any effects of the alpha radiation on the metastases and observe the potential changes in 68Ga-PSMA I&T uptake. Eight weeks after the first cycle, patients will receive the second cycle of 225Ac-PSMA I&T. If no Dose Limiting Toxicity (DLT) occurs, the dose can be increased for the next DL. If a DLT occurs, the cohort will be expanded to 6 patients. After establishing the recommended dose, an expansion cohort will be opened with a total of 12 patients. Main study endpoints: To investigate the safety, tolerability and biochemical effects of 225Ac-PSMA I&T injected in patients with metastatic prostate cancer. Primary objective: - To assess the safety and tolerability of 225Ac-PSMA I&T administered intravenously Secondary objectives: To predict and calculate the absorbed-dose in critical organs (e.g. salivary glands, kidneys, bone marrow) by 68Ga-PSMA I&T PET-MRI To evaluate the effects of the radionuclide therapy on metastases in the days after therapy using 68Ga-PSMA I&T PET-MRI To evaluate the biochemical effects of 225Ac-PSMA I&T therapy in patients with metastatic prostate cancer

Official Title
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Phase I Dose Escalation Study to Evaluate Tolerability and Safety of 225Ac-PSMA I&T in Patients With Metastatic Prostate Cancer

Conditions
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Prostatic Neoplasms, Castration-Resistant

Intervention / Treatment
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* Radiation: Radionuclide Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathological proven metastatic castration resistant prostate cancer. Castrationresistant disease is defined as a serum testosterone level of 50 nanogram per deciliter or lower (≤1.7 nanomol per liter) after bilateral orchiectomy or during maintenance treatment consisting of androgen-ablation therapy with a luteinizing hormone-releasing hormone agonist. Evidence of progressive disease, defined as 1 or more Prostate Cancer Work Grouping 3 (PCWG3) criteria: - PSA level ≥ 1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart Progression as defined by RECIST 1.1 with PCGW3 modifications Progression after at least one line of chemotherapy and/or one line of nonsteroidal antiandrogen (NSAA). No active anti-tumor therapy, except for androgen deprivation therapy in combination with at least one androgen receptor-targeted agent Willing and able to undergo 2 cycles of 225Ac-PSMA I&T therapy and 3 PET-MRI scans in 16 weeks and comply with protocol Signed and dated written informed consent by the patient (or legal representative) prior to any study-specific procedures. Age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance-status score 0-2. Use of highly effective methods of contraception (female partners of male participants) During the trial and 6 months after completion of the study or willing to practice sexual abstinence. Exclusion Criteria: Concurrent severe illness or clinically relevant trauma within 2 weeks before the administration of the investigational product that might preclude study completion or interfere with study results Serum hemoglobin ≤ 6.2 mmol/L, total white blood cell (WBC) count ≤ 3.5·109/L, absolute neutrophil count ≤ 1.5·109/L, platelet count ≤ 100·109/L, serum creatinine concentration ≥ 150 umol/L (≥ 1.7 mg/dL), serum albumin <30 g/L, bilirubin ≥ 1.5 x upper limit normal (ULN), aspartate transaminase (ASAT) ≥ 3 x ULN and alanine aminotransferase (ALAT) ≥ 3 x ULN (or bilirubin ≥ 3 x ULN, ASAT ≥ 5 x ULN and ALAT ≥ 5 x ULN in the case of pre-existing liver metastases at baseline) Concurrent bladder outflow obstruction or unmanageable urinary incontinence Known or expected hypersensitivity to Gallium-68, Actinium-225, PSMA I&T, or any excipient present in 225Ac/68Ga-PSMA I&T Prior administration of a radiopharmaceutical within a period corresponding to 8 halflives of the radionuclide used on such radiopharmaceutical Prior treatment with any radionuclide therapy History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study Central nervous system (CNS) metastases, leptomeningeal disease, or spinal cord compression Radiation therapy within 4 weeks of first dose (or local or focal radiotherapy within 2 weeks of first dose) Male subjects unwilling to abstain from donating sperm during treatment and for an additional 6 months after the last dose

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
Interventional Model Description: A clinical prospective, single-center, single-arm, phase I dose escalation therapy study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 225Ac-PSMA I&T<br>225Ac-PSMA I&T | Radiation: Radionuclide Therapy<br>* To evaluate the tolerability and safety of 225Ac-PSMA I&T in patients with metastatic prostate cancer<br>* Other names: 225Ac-PSMA I&T;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of Adverse Events and Serious Adverse Events as assessed by CTCAE v5.0 | Safety and tolerability assessment | 4 years | 
| Absolute values and changes from baseline in laboratory parameters (hematology, blood chemistry and urinalysis), including assessment of shifts from baseline to abnormal values on treatment | Safety and tolerability assessment | 4 years | 
| Absolute values and changes from baseline in vital signs & ECG parameters | Safety and tolerability assessment | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To predict and calculate the absorbed-dose in critical organs (e.g. salivary glands, kidneys, bone marrow) by 68Ga-PSMA I&T PET-MRI | Dosimetry | 4 years | 
| Changes in SUVmax of the target lesions on PET-MRI and morphological changes evaluated on MRI | Direct effect of 225Ac-PSMA I&T | 4 years | 
| Objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria v.1.1. | Preliminary efficacy | 4 years | 
| Percent changes from baseline in tumor size where tumor size is defined as the sum of all target lesions as measured by RECIST criteria v.1.1. | Preliminary efficacy | 4 years | 
| Prostate Specific Antigen(PSA) response rate assessed from treatment visit 1 defined as a decrease in PSA of ≥ 50% from baseline. | Preliminary efficacy | 4 years | 
| Percent change from baseline in PSA as a continuous endpoint by visit and maximum reduction during the study | Preliminary efficacy | 4 years | 
| Percent change from baseline values of pain questionnaire at every treatment visit | Preliminary efficacy | 4 years | 
| Overall Survival (OS) defined as the time from the date of first dose of 225Ac-PSMA I&T treatment to the date of death due to any cause. | Preliminary efficacy | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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225Ac-PSMA, Prostate cancer