A Phase 2/3, Randomized, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of FPI-2265 (225Ac-PSMA-I&T) in Patients With PSMA-Positive Metastatic Castration-Resistant Prostate Cancer (mCRPC), Previously Treated With 177Lu-PSMA Radioligand Therapy (RLT)

This is an open-label, randomized, multicenter study of FPI-2265 (225Ac-PSMA-I\&T). Patient population is adult participants with PSMA positive mCRPC who have had previous treatment with with 177Lu-PSMA-617 or another 177Lu-PSMA radioconjugate (RC). The purpose of the study is to determine the safety and tolerability, and recommended dose and regiment of FPI-2265.

More details:

This is an open-label, randomized, multicenter study of FPI-2265 (225Ac-PSMA-I\&T). The purpose of the dose optimization segment (Phase 2) is to determine the recommended FPI-2265 dose and regimen. Conclusions from Phase 2 will be based on safety, tolerability, and anti-tumor activity. Screening Period: At screening, participants will be assessed for eligibility and undergo a positron emission tomography (PET)/computed tomography (CT) scan to evaluate PSMA positivity. Only participants with PSMA positive cancer and confirmed eligibility criteria will be randomized. Participants randomized will enter the treatment period and receive investigational doses of FPI2265 according to the dose level and schedule as specified per proposed dose arm. Part A participants will enroll 1:1:1 at three dose level/schedules, to arms 1, 2 or 3 Part B participants will enroll after completion of part A, in a 1:1 randomization scheme to arms 6 or 7. Once Part A is fully enrolled and participants have been followed for at least 12 weeks, data from Arm 1 and 2 will be analyzed to assess the the feasibility of enrolling participants to arms 4 and 5. All participants will be monitored and assessed for efficacy response, disease progression and adverse events. Supportive care will be allowed in all arms at the discretion of the investigator and includes available care for the eligible participant according to best institutional practice for mCRPC treatment, including androgen deprivation therapy (ADT). Follow-up after end of treatment visit will proceed for 5 years. 5 participants will be enrolled into a dosimetry substudy (open at select sites only). Dosimetry substudy participants will be administered one dose at of FPI2265 and proceed with dosimetric assessments will be taken at a number of timepoints after dose administration.

Overview

FPI-2265 (225Ac-PSMA-I&T) is an investigational, small‑molecule radioconjugate that targets prostate‑specific membrane antigen (PSMA) and delivers the alpha‑emitter actinium‑225. It is being developed for metastatic castration‑resistant prostate cancer (mCRPC), including patients previously treated with 177Lu‑based PSMA radioligand therapy. Phase 2/3 studies are ongoing and actively enrolling. (fusionpharma.com)

Mechanism of action

• Target: PSMA, highly expressed on most prostate cancer cells.
• Modality: PSMA‑I&T small‑molecule ligand linked to actinium‑225, an alpha‑particle emitter with short path length and high linear energy transfer, designed to induce clustered DNA double‑strand breaks while limiting off‑target tissue exposure. (fusionpharma.com)

Efficacy

Interim Phase 2 (TATCIST) poster (data cutoff March 1, 2024; 35 treated, 25 with ≥12 weeks’ follow‑up; 20 efficacy‑evaluable after prespecified exclusions):
- PSA50 response (≥50% decline by week 12): 50% (10/20) overall; 54–61% in lutetium‑naïve and 42–43% in prior‑lutetium patients.
- Exploratory subset with baseline PSMA SUVmean >6 (n=13; 6 with prior lutetium): PSA50 in 69% (9/13).
- RECIST v1.1 (independent review; n=9 with measurable soft‑tissue disease): partial response 33% (3/9); stable disease 44% (4/9).
- PCWG3 composite: non‑progressive disease in 70% (14/20).
These findings indicate antitumor activity in heavily pretreated patients, including after prior 177Lu‑PSMA radioligand therapy. (fusionpharma.com)

Earlier, small prospective/retrospective experiences with 225Ac‑PSMA‑I&T in advanced mCRPC reported PSA50 responses in 7/14 patients and manageable hematologic toxicity, supporting biological activity of this construct. (pubmed.ncbi.nlm.nih.gov)

Safety

In the TATCIST interim analysis (safety population n=25):
- Most treatment‑related adverse events (TRAEs) were grade 1–2.
- Xerostomia was the most common TRAE; the poster describes predominantly grade 1–2 events, and the sponsor’s summary specifies 62% grade 1 and 24% grade 2.
- Hematologic TRAEs (anemia, thrombocytopenia), fatigue, and dry eye were also observed.
- One treatment‑related death (cerebral hemorrhage) occurred in a patient with a superscan pattern; superscan patients were excluded from efficacy analyses after a protocol amendment. (fusionpharma.com)

A prospective Phase I dose‑escalation study of 225Ac‑PSMA‑I&T (NCT05902247) is separately assessing tolerability and dosimetry to inform dosing; the published protocol underscores the need to define optimal activity due to xerostomia and hematologic risks observed with alpha‑PSMA agents. (bmccancer.biomedcentral.com)

Ongoing trials

• TATCIST Phase 2/3, randomized, open‑label, multicenter study in PSMA‑positive mCRPC previously treated with 177Lu‑PSMA RLT; currently enrolling at multiple centers (e.g., MD Anderson). (mdanderson.org)

Further reading

• Preliminary efficacy and safety results from the TATCIST trial (AACR 2024 poster; PDF). (fusionpharma.com)
• Sponsor summary of TATCIST interim data (AACR 2024 press release). (prnewswire.com)
• First clinical results for 225Ac‑PSMA‑I&T in advanced mCRPC (retrospective series). (pubmed.ncbi.nlm.nih.gov)
• 225Ac‑PSMA‑I&T Phase I dose‑escalation protocol (BMC Cancer; NCT05902247). (bmccancer.biomedcentral.com)

Note: Phase 2/3 development is ongoing; efficacy and safety data are interim and may evolve with larger, controlled cohorts. (fusionpharma.com)

Last updated: Oct 2025

Key Inclusion Criteria:

* Phase 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

* Diagnosis of adenocarcinoma of prostate proven by histopathology.

* Must have had prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum/plasma testosterone

* Progressive mCRPC at time of study entry.

* Must have been previously treated with lutetium-PSMA therapy (lutetium-177 vipivotide tetraxetan or other lutetium-177-PSMA RLT). Treatment must have been completed \>6 weeks prior to the first dose of study drug.

* Participants with known BRCA mutations should have received FDA-approved therapies such as PARP inhibitors, per Investigator discretion.

* Positive PSMA PET/CT scan

* Adequate organ function

* For participants who have partners of childbearing potential: Partner and/or participant must not be planning to conceive and must use a method of birth control with adequate barrier protection deemed acceptable by the Principal Investigator during the study treatment and for six months after last study drug administration.

Key Exclusion Criteria:

* Participants who received more than two prior lines of cytotoxic chemotherapy for CRPC.

* Phase 2: participants who progress prior to administration of the 3rd cycle of prior treatment with 177Lu-PSMA therapy

* All prior treatment-related adverse events must have resolved to Grade ≤1 (CTCAE v5.0). Alopecia and stable persistent Grade 2 peripheral neuropathy may be allowed at the discretion of the Investigator.

* Participants with known, unresolved, urinary tract obstruction are excluded.

* Administration of any systemic cytotoxic or investigational therapy ≤30 days of the first dose of study treatment or five half-lives, whichever is shorter. Completion of large-field external beam radiotherapy ≤four weeks of the first dose of study treatment.

* Participants with a history of central nervous system (CNS) metastases are excluded except those who have received therapy

* Participants with any liver metastases will be excluded from the Phase 2 segment of the study.

* Participants with skeletal metastases presented as a superscan on a ⁹⁹ᵐTc bone scan.

* Previous or concurrent cancer that is distinct from the cancer under investigation in primary site or histology, except treated cutaneous basal cell carcinoma or squamous cell carcinoma and superficial bladder tumors. Any cancer curatively treated \>two years prior to the first dose of treatment is permitted.

* Concurrent serious (as determined by the investigator) medical conditions

* Major surgery ≤30 days prior to the first dose of study treatment.