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.

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

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

Male