[225Ac]Ac-PSMA-R2 for Prostate Cancer

(SatisfACtion Trial)

Recruiting at 14 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Novartis Pharmaceuticals

Must be taking: ADT

Must not be taking: Investigational agents

Disqualifiers: CNS metastases, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label, phase I/II, multi-center study in adult participants with metastatic hormone sensitive prostate cancer (mHSPC) and with metastatic castration resistant prostate cancer (mCRPC) who have received prior anti-cancer treatment and have a positive 68Ga-PSMA-11 PET scan. The purpose of this study is to learn if the study drug, \[225Ac\]Ac-PSMA-R2, is safe and tolerable, and has anti-tumor activity in treated patients.

Do I need to stop my current medications for the trial?

The trial requires that you stop any investigational agents and systemic anti-cancer therapies at least 28 days before starting the study drug. The protocol does not specify other medications, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment [225Ac]Ac-PSMA-R2 for prostate cancer?

Research shows that [225Ac]Ac-PSMA treatment has been promising for patients with advanced prostate cancer who did not respond to other therapies. In a study, 58% of patients experienced a decline in prostate-specific antigen (PSA) levels, indicating a positive response to the treatment. ^{1 2 3 4 5}

Is [225Ac]Ac-PSMA-R2 safe for humans?

[225Ac]Ac-PSMA-R2 has been tested in patients with advanced prostate cancer, showing promising results with minimal treatment-related organ toxicity. However, it can cause significant damage to healthy tissues if not properly targeted, and some patients experienced side effects like dry mouth and kidney issues. ^{1 3 4 5 6}

How is the drug [225Ac]Ac-PSMA-R2 different from other prostate cancer treatments?

[225Ac]Ac-PSMA-R2 is unique because it uses Actinium-225, an alpha emitter, which is expected to be more effective and have fewer side effects than treatments using beta emitters like Lutetium-177. This drug is particularly promising for patients with advanced prostate cancer who have not responded to other treatments. ^{1 3 5 7 8}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for adults with metastatic hormone sensitive or castration resistant prostate cancer who've had prior treatments and show PSMA-positive disease on a PET scan. They must have adequate organ function, and some should have received prior 177Lu-PSMA therapy.

Inclusion Criteria

My organs are working well.

My prostate cancer is worsening despite treatment.

My cancer shows PSMA-positive on a PET/CT scan.

Exclusion Criteria

Any other investigational agents within 28 days of the anticipated C1D1 of 225Ac-PSMA-R2 therapy

I have had a heart attack, chest pain, or heart surgery in the last 6 months.

I haven't had cancer treatment in the last 28 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose or Recommended Dose for Expansion (MTD/RDE)

Up to 6 weeks

Multiple visits for dose escalation meetings and safety assessments

Dose Expansion

Participants receive the recommended dose of 225Ac-PSMA-R2 to assess anti-tumor activity

Assessed up to approximately 15 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 months after the last dose

Safety follow-up visits

Treatment Details

Interventions

• [225Ac]Ac-PSMA-R2

Trial Overview The study tests the safety, tolerability, and anti-tumor effects of [225Ac]Ac-PSMA-R2 in patients with progressive metastatic prostate cancer. It's an open label phase I/II trial that includes participants who have/haven't received previous 177Lu-PSMA therapy.

Participant Groups

Group I: Group-2 (mCRPC/ pre-177Lu) Experimental Treatment 3 Interventions

1. Dose Escalation: All eligible participants with mCRPC who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), prior taxane-based chemotherapy is not required, but have never been treated with 177Lu-labelled PSMA-targeted RLT (177Lu-labelled PSMA-targeted RLT treatment naïve) will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 2. 2. Dose Expansion: Once RDE is determined for Group 2, participants naïve to 177Lu-labelled PSMA-targeted Radioligand Therapy (RLT) will be enrolled in Group 2 dose expansion.

Group II: Group-1 (mCRPC/ post-177Lu) Experimental Treatment 3 Interventions

1. Dose Escalation: All eligible participants with Metastatic Castration Resistant Prostate Cancer (mCRPC) who have received anti-cancer treatment (post-Androgen Receptor Pathway Inhibitors (ARPI), post-taxane based chemotherapy and heavily pre-treated and having already received prior 177Lu-labelled Prostate Specific Membrane Antigen (PSMA)-targeting Radioligand Therapy (RLT) will receive the starting dose of 7 Megabecquerel (MBq) of 225Ac-PSMA-R2 to determine the Maximum Tolerated Dose/Recommended Dose for Expansion (MTD/RDE) of Group 1. 2. Dose Expansion: Once RDE is determined for Group 1, participants who have previously received 177Lu-PSMA-RLT will be enrolled in Group 1 dose expansion.

Group III: Group 3 (mHSPC/ pre-177Lu) Experimental Treatment 3 Interventions

1. Dose Escalation: All eligible participants with mHSPC (177Lu-labelled PSMA-targeted RLT treatment naïve), who are treatment naive or minimally treated with a) luteinizing hormone-releasing hormone (LHRH) agonist/antagonists or bilateral orchiectomy with or without first generation antiandrogen (e.g. bicalutamide, flutamide) b) CYP17 inhibitor or ARDT exposure. Patient in this group will start treatment with 225Ac-PSMA-R2 after group 1 and group 2 patients. 2. Dose Expansion: Once RDE is determined for Group 3, participants will be enrolled in Group 3 dose expansion.

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

In a study of 23 patients with advanced-stage metastatic castration-resistant prostate cancer (mCRPC) who were unresponsive to [177Lu]Lu-PSMA therapy, [225Ac]Ac-PSMA treatment demonstrated a safety profile with manageable side effects, including some cases of grade 3 hematologic and nephrotoxicity.

The treatment showed potential efficacy, with 26% of patients achieving a significant decline in prostate-specific antigen (PSA) levels and a disease control rate of 50%, indicating that [225Ac]Ac-PSMA could be a viable option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Experience with [225Ac]Ac-PSMA Treatment in Patients with [177Lu]Lu-PSMA-Refractory Metastatic Castration-Resistant Prostate Cancer. Alan-Selcuk, N., Beydagi, G., Demirci, E., et al.[2023]

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]

Actinium-225 (Ac-225) PSMA radioligand therapy (RLT) shows promising efficacy in treating metastatic castration-resistant prostate cancer (mCRPC), with 81% of patients experiencing a decline in PSA levels and 60% achieving more than a 50% reduction.

The treatment is generally safe, with the most common side effect being mild to moderate xerostomia (dry mouth) reported in 73.9% of patients, indicating that Ac-225 may have fewer severe side effects compared to traditional beta-emitting therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Actinium-225 Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Prostate Cancer: A Systematic Review and Metanalysis. Parida, GK., Panda, RA., Bishnoi, K., et al.[2023]

177Lu-PSMA is an effective treatment for advanced prostate cancer, lowering PSA levels and improving quality of life, but about one-third of patients may not respond well to this therapy, highlighting the need for better personalization of treatment.

225Ac-PSMA shows promise for tumors resistant to standard treatments, offering a better response than 177Lu-PSMA, but it poses risks of significant damage to healthy tissues, necessitating careful dosimetry and potential use of nano-carriers for safer delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of 177Lutetium-PSMA and 225Actinium-PSMA as Emerging Theranostic Agents in Prostate Cancer. Alam, MR., Singh, SB., Thapaliya, S., et al.[2022]

In a study of 11 heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC), treatment with Actinium-225 (225Ac) labeled PSMA-617 led to a significant improvement in quality of life, as measured by the NCCN-FACT-FPSI-17 questionnaire, particularly in physical and emotional symptoms.

The therapy resulted in a notable biochemical response, with 46% of patients experiencing a significant decline in Prostate Specific Antigen (PSA) levels, while the treatment was associated with manageable side effects, including some Grade 3 toxicities in a small number of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality-of-Life Outcomes with Actinium-225-Prostate-Specific Membrane Antigen-617 Therapy in Patients with Heavily Pretreated Metastatic Castration-Resistant Prostate Cancer. Satapathy, S., Mittal, BR., Sood, A., et al.[2022]

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]

Targeted alpha-particle therapy with 225Ac-PSMA shows promise as a treatment for metastatic castration-resistant prostate cancer (mCRPC), with a low morbidity profile, but the evidence is still limited due to the low quality of available trials.

Patients who previously received 177Lu-PSMA therapy may experience reduced efficacy from subsequent 225Ac-PSMA treatment, indicating a potential radioresistance effect that needs further investigation through randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to RL-225Ac in prostate cancer: Effect of prior treatment with RL-177Lu: A systematic review of the literature. Stangl-Kremser, J., Ricaurte-Fajardo, A., Subramanian, K., et al.[2023]

The study presents an optimized protocol for preparing Ac-225 labeled with PSMA-617, achieving a high yield of 85%-87% and radiochemical purity of 97%-99%, which is crucial for effective targeted alpha therapy in prostate cancer.

This method allows for a single-step, routine in-house radiolabeling process, making it a practical approach for delivering targeted treatment to patients with metastatic castration-resistant prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In-House Preparation and Quality Control of Ac-225 Prostate-Specific Membrane Antigen-617 for the Targeted Alpha Therapy of Castration-Resistant Prostate Carcinoma. Thakral, P., Simecek, J., Marx, S., et al.[2022]

References

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

Clinical Experience with [225Ac]Ac-PSMA Treatment in Patients with [177Lu]Lu-PSMA-Refractory Metastatic Castration-Resistant Prostate Cancer. [2023]

2. 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]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Actinium-225 Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Prostate Cancer: A Systematic Review and Metanalysis. [2023]

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

A Review of 177Lutetium-PSMA and 225Actinium-PSMA as Emerging Theranostic Agents in Prostate Cancer. [2022]

5. India pubmed.ncbi.nlm.nih.gov

Health-Related Quality-of-Life Outcomes with Actinium-225-Prostate-Specific Membrane Antigen-617 Therapy in Patients with Heavily Pretreated Metastatic Castration-Resistant Prostate Cancer. [2022]

6. 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]

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

Response to RL-225Ac in prostate cancer: Effect of prior treatment with RL-177Lu: A systematic review of the literature. [2023]

8. India pubmed.ncbi.nlm.nih.gov

In-House Preparation and Quality Control of Ac-225 Prostate-Specific Membrane Antigen-617 for the Targeted Alpha Therapy of Castration-Resistant Prostate Carcinoma. [2022]