Actium-225-Prostate Specific Membrane Antigen Imaging & Therapy (225AcPSMAI&T)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Prostatic Neoplasms, Castration-Resistant
• Intervention / Treatment: Radiation: Radionuclide Therapy

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Sui wai Ling; Phone Number: +31107033612; Email: s.ling@erasmusmc.nl
• Study Contact Backup: Name: Laurens Groenendijk; Phone Number: +31107033612; Email: imaging.trialbureau@erasmusmc.nl

Study Locations

• Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015GD
      • Recruiting
      • Erasmus Medical Center
      • Contact: Laurens Groenendijk; Phone Number: +31107033612; Email: imaging.trialbureau@erasmusmc.nl
      • Contact: Sui wai Ling Ling; Phone Number: +31107033612; Email: s.ling@erasmusmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Dutch Cancer Society

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2021
• Primary Completion (Estimated): December 29, 2025
• Study Completion (Estimated): December 29, 2025

Study Registration Dates

• First Submitted: May 24, 2023
• First Submitted That Met QC Criteria: June 5, 2023
• First Posted (Estimated): June 13, 2023

Study Record Updates

• Last Update Posted (Estimated): June 13, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Prostate cancer; 225Ac-PSMA
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant
• Other Study ID Numbers: NL73234.078.20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No