actium-225-prostate specific membrane antigen imaging & therapy

Conditions: Prostatic Neoplasms, Castration-Resistant

Summary: 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

Eligibility criteria:
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

Keywords: 225ac-psma prostate cancer