FPI-2265 for Metastatic Prostate Cancer

(AlphaBreak Trial)

Recruiting at 17 trial locations

Overseen By Clinical Trials Fusion Pharmaceuticals Inc.

Age: 18+

Sex: Male

Trial Phase: Phase 2 & 3

Sponsor: Fusion Pharmaceuticals Inc.

Must be taking: Androgen-deprivation therapy

Must not be taking: Cytotoxic chemotherapy

Disqualifiers: CNS metastases, Liver metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 0

Duration: 16-32 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had any systemic cytotoxic or investigational therapy within 30 days before the first dose of the study treatment.

What data supports the effectiveness of the drug FPI-2265 for metastatic prostate cancer?

Research shows that similar treatments using 225Ac-PSMA, like 225Ac-PSMA-617, have been effective in reducing symptoms and imaging lesions in patients with metastatic prostate cancer, with some patients experiencing no adverse effects. ^{1 2 3 4 5}

What safety data exists for FPI-2265 (225Ac-PSMA-I&T) in humans?

In a study with 14 patients using 225Ac-PSMA-I&T for advanced prostate cancer, no acute toxicity was observed during treatment. Some patients experienced side effects like anemia (low red blood cell count) and leukopenia (low white blood cell count), but these were generally manageable. Additionally, mild to moderate dry mouth was noted in some patients. ^{5 6 7 8 9}

What makes the drug FPI-2265 unique for treating metastatic prostate cancer?

FPI-2265 (225Ac-PSMA-I&T) is unique because it uses targeted alpha therapy (TAT) to deliver alpha-particle radiation directly to prostate cancer cells that express PSMA (prostate-specific membrane antigen), which can be effective even when other treatments have failed. This approach is promising for patients with advanced metastatic castration-resistant prostate cancer, especially those who have not responded to or have developed resistance to other therapies like 177Lu-PSMA. ^{2 3 6 10 11}

Research Team

Keith Barnett

Principal Investigator

Fusion Pharmaceuticals Inc.

Eligibility Criteria

This trial is for individuals with metastatic castration-resistant prostate cancer (mCRPC) that shows PSMA positivity. Participants must have previously undergone treatment with a specific type of radioligand therapy using 177Lu-PSMA.

Inclusion Criteria

My prostate cancer is worsening despite treatment.

My prostate cancer was confirmed through a tissue examination.

Ability to understand and sign an approved informed consent form (ICF) and comply with all protocol requirements

Exclusion Criteria

I have had more than two chemotherapy treatments for prostate cancer.

Concurrent serious (as determined by the investigator) medical conditions

I have not had major surgery in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive FPI-2265 in one of three dosing regimens: Arm 1 (9 doses every 4 weeks), Arm 2 (6 doses every 6 weeks), or Arm 3 (4 doses every 8 weeks)

16-32 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of PSA50 response and adverse events

12 weeks

Long-term follow-up

Participants are monitored for long-term safety and efficacy, including treatment-emergent adverse events

5 years

Treatment Details

Interventions

• FPI-2265 (225Ac-PSMA-I&T)

Trial Overview The study is testing FPI-2265, a new drug targeting PSMA-positive cells in mCRPC patients. It's an open-label and multicenter trial aiming to find the best dose by looking at safety, tolerability, and how well it works against tumors.

Participant Groups

Group I: Part B Arm 7 Experimental Treatment 1 Intervention

Group II: Part B Arm 6 Experimental Treatment 1 Intervention

Group III: Part B Arm 5 Experimental Treatment 1 Intervention

to be utilized based on analysis of Part A

Group IV: Part B Arm 4 Experimental Treatment 1 Intervention

to be utilized based on analysis of Part A

Group V: Part A Arm 3 Experimental Treatment 1 Intervention

Group VI: Part A Arm 2 Experimental Treatment 1 Intervention

Group VII: Part A Arm 1 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Fusion Pharmaceuticals Inc.

Lead Sponsor

Trials

6

Recruited

590+

Findings from Research

In a systematic review of 141 patients with metastatic castration-resistant prostate cancer (mCRPC), 225 Ac-PSMA-targeted alpha therapy (TAT) showed a significant biochemical response, with 83% of patients experiencing any decline in prostate-specific antigen (PSA) levels and 59% achieving more than a 50% decline.

The treatment also demonstrated promising overall survival rates of 81% and a median progression-free survival of 12 months, while maintaining low toxicity, with the most common side effects being mild dry mouth and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225 Ac-PSMA-617-targeted alpha therapy for the treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis. Ballal, S., Yadav, MP., Sahoo, RK., et al.[2021]

A case study demonstrated that 225 Ac-PSMA-617 therapy led to remission of clinical symptoms and imaging lesions in a patient with metastatic castration-resistant prostate cancer after 4 treatment cycles.

The patient experienced no observable adverse effects, suggesting that 225 Ac-PSMA-617 may be a safe and effective alternative for those who do not respond to 177 Lu-PSMA therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Multiple Bone Metastases of Castration-Resistant Prostate Cancer With 225 Ac-PSMA-617. Yang, H., Zhang, Y., Su, D., et al.[2023]

In a study of 12 patients with metastatic castration-resistant prostate cancer, 225Ac-PSMA therapy showed promising results, with 9 out of 12 patients exhibiting a PSA response after the first treatment cycle, and 6 achieving a significant reduction of over 50%.

The median overall survival for patients who responded to the therapy was 10 months, compared to 4 months for non-responders, suggesting that early PSA response may correlate with better survival outcomes, although the difference was not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-Prostate-Specific Membrane Antigen Therapy for Castration-Resistant Prostate Cancer: A Single-Center Experience. Sanli, Y., Kuyumcu, S., Simsek, DH., et al.[2023]

The PSMA inhibitor (PSMA I&T) demonstrated strong binding affinity to prostate-specific membrane antigen (PSMA) and showed effective tumor targeting in preclinical models, indicating its potential for imaging and therapy in metastatic prostate cancer.

Initial human studies using (68)Ga-PSMA I&T for PET imaging successfully detected metastatic lesions with high contrast, and (177)Lu-PSMA I&T treatment in two patients was effective and safe, showing no detectable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. Weineisen, M., Schottelius, M., Simecek, J., et al.[2018]

The study of 32 patients with metastatic castration-resistant prostate cancer (mCRPC) showed that the radiolabeled antibody 225Ac-J591 is safe, with a maximum tolerated dose not reached and only one patient experiencing dose-limiting toxicity.

Preliminary efficacy results indicated that 46.9% of patients had at least a 50% decline in prostate-specific antigen (PSA) levels, and 59.1% showed a response in circulating tumor cell counts, suggesting potential effectiveness of this novel therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591. Tagawa, ST., Thomas, C., Sartor, AO., et al.[2023]

In a study of 14 patients with advanced metastatic castration-resistant prostate cancer, treatment with 225Ac-PSMA imaging and therapy (I&T) showed promising results, with 50% or greater declines in prostate-specific antigen (PSA) levels observed in 7 patients.

The treatment was well-tolerated, with no acute toxicity during hospitalization, although some patients experienced grade 3 anemia and leukopenia; importantly, preexisting xerostomia did not worsen in most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First Clinical Results for PSMA-Targeted α-Therapy Using 225Ac-PSMA-I&T in Advanced-mCRPC Patients. Zacherl, MJ., Gildehaus, FJ., Mittlmeier, L., et al.[2021]

The new α-particle-emitting compound 225Ac-L1 shows specific targeting and effective cell kill in prostate cancer cells that express PSMA, demonstrating significant tumor growth inhibition and improved survival in xenograft models.

While 225Ac-L1 has promising efficacy, it also presents some off-target radiotoxicity, particularly in the kidneys and liver, with a maximum tolerated dose estimated at about 1 MBq/kg, indicating a need for careful dosing in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of 213Bi- and 225Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer. Banerjee, SR., Lisok, A., Minn, I., et al.[2022]

The FDA has approved 177Lu-PSMA-617 for treating advanced metastatic castrate-resistant prostate cancer (mCRPC), marking a significant advancement in PSMA-targeted therapies.

Various PSMA-targeted radiopharmaceuticals, including both beta and alpha emitters, are in development, with promising results for alpha therapies like 225Ac-PSMA-617, although there are concerns about potential toxicity to salivary and renal tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts. Sartor, O., Baghian, A.[2022]

The study demonstrated that 99mTc-EDDA/HYNIC-iPSMA has a high tumor uptake in prostate cancer patients, with an average tumor/background ratio of 8.99, indicating its potential as an effective imaging agent for targeting prostate cancer.

The safety profile of 99mTc-EDDA/HYNIC-iPSMA was confirmed, as the absorbed radiation doses were comparable to those of other 99mTc studies, with an effective dose of 3.42 mSv, suggesting it is a safe option for imaging in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

99mTc-labeled PSMA inhibitor: Biokinetics and radiation dosimetry in healthy subjects and imaging of prostate cancer tumors in patients. Santos-Cuevas, C., Davanzo, J., Ferro-Flores, G., et al.[2018]

In a study of 56 patients with metastatic castration-resistant prostate cancer (mCRPC) who had exhausted standard treatments, [225Ac]Ac-PSMA-617 targeted alpha therapy showed promising efficacy, with 91% of patients experiencing a decline in prostate-specific antigen (PSA) levels, and a median overall survival of 15 months.

The treatment was well-tolerated, with most adverse events being mild to moderate, such as transient fatigue in 70% of patients and xerostomia in about one-third, indicating that [225Ac]Ac-PSMA-617 could be a viable option for patients with advanced mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study. Ballal, S., Yadav, MP., Satapathy, S., et al.[2023]

Targeted alpha therapy using 225Ac-labeled PSMA-617 has shown remarkable therapeutic efficacy in treating metastatic castration-resistant prostate cancer, highlighting its potential as a treatment option.

The review also discusses the production methods for 225Ac and its daughter nuclide 213Bi, along with clinical experiences in using these alpha emitters for various cancers, including bladder cancer and brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Overview of Targeted Alpha Therapy with 225Actinium and 213Bismuth. Morgenstern, A., Apostolidis, C., Kratochwil, C., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

225 Ac-PSMA-617-targeted alpha therapy for the treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Treatment of Multiple Bone Metastases of Castration-Resistant Prostate Cancer With 225 Ac-PSMA-617. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

225Ac-Prostate-Specific Membrane Antigen Therapy for Castration-Resistant Prostate Cancer: A Single-Center Experience. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

First Clinical Results for PSMA-Targeted α-Therapy Using 225Ac-PSMA-I&T in Advanced-mCRPC Patients. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of 213Bi- and 225Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

99mTc-labeled PSMA inhibitor: Biokinetics and radiation dosimetry in healthy subjects and imaging of prostate cancer tumors in patients. [2018]

10. Germany pubmed.ncbi.nlm.nih.gov

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study. [2023]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

An Overview of Targeted Alpha Therapy with 225Actinium and 213Bismuth. [2019]