[Ac-225]-PSMA-62 for Prostate Cancer

(ACCEL Trial)

Recruiting at 9 trial locations

Overseen By Richard Cioci

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company

Must not be taking: PSMA-directed radioligands, Systemic radionuclides

Disqualifiers: Urinary obstruction, Liver metastases, others

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

Compensation: Varies

Number of Visits: Unknown

142 Participants Needed

Trial Summary

What is the purpose of this trial?

ACCEL is a multicenter, open label phase Ia/Ib/II study of \[Ac-225\]-PSMA-62 in participants with prostate-specific membrane antigen (PSMA)-positive prostate cancer.

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 received any investigational therapeutic agents within 4 weeks or 5 half-lives of starting the study treatment.

What data supports the effectiveness of the treatment [Ac-225]-PSMA-62 for prostate cancer?

Research on similar treatments, like 225Ac-PSMA-617, shows promising results in treating advanced prostate cancer by targeting cancer cells specifically, which can improve survival outcomes. Additionally, studies on related compounds, such as [225Ac]Ac-PNT-DA1, have demonstrated effective tumor shrinkage with minimal toxicity, suggesting potential benefits for [Ac-225]-PSMA-62. ^{1 2 3 4 5}

Is [Ac-225]-PSMA-62 safe for human use?

Research on similar treatments like [225Ac]Ac-PSMA-617 shows promising results, but there are concerns about potential side effects, particularly related to salivary and kidney toxicity. While it has shown good responses in advanced prostate cancer, more studies are needed to fully understand its safety profile. ^{3 6 7 8 9}

What makes the drug [Ac-225]-PSMA-62 unique for prostate cancer treatment?

[Ac-225]-PSMA-62 is unique because it uses targeted alpha therapy (TAT) to deliver alpha-particle radiation directly to prostate cancer cells that express prostate-specific membrane antigen (PSMA), potentially offering a new option for patients with advanced prostate cancer who have not responded to other treatments. ^{1 2 3 10 11}

Research Team

Richard Cioci

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

This trial is for adults over 18 with advanced prostate cancer that's resistant to hormone therapy and has come back after treatment. They must have good organ function, an ECOG performance status of 0-2, a life expectancy of at least 6 months, and agree to use two forms of contraception. People with HIV can join if they're healthy. Participants should be out of other treatment options.

Inclusion Criteria

Patients and their female partner(s) of childbearing potential must agree to use two acceptable forms of contraception, one of which must be a barrier method during the study and for 21 weeks after last study drug administration

The patient has read, understood, and signed the written informed consent form(s)

Criteria specific for patients with mCRPC:

Exclusion Criteria

My cancer has spread to my liver.

My prostate cancer is of the neuroendocrine or small cell type.

Inability to lie flat during or tolerate PET/CT or MRI

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ia Treatment

Evaluation of safety and tolerability to determine the maximum tolerated dose (MTD) of [Ac-225]-PSMA-62

4 weeks

Multiple visits for dose administration and monitoring

Phase Ib Treatment

Randomized dose optimization to determine the recommended phase II doses (RP2D)

16-24 weeks

Regular visits for treatment and monitoring of adverse events

Phase II Treatment

Evaluation of efficacy of [Ac-225]-PSMA-62 in patients with mCRPC

16-24 weeks

Regular visits for treatment and efficacy assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Periodic visits for long-term monitoring

Treatment Details

Interventions

• [Ac-225]-PSMA-62

Trial Overview [Ac-225]-PSMA-62 is being tested in this phase I/II study on patients whose prostate cancer cells have PSMA. The trial aims to see how safe it is and how well it works across multiple centers where everyone knows what treatment they're getting.

Participant Groups

Group I: mCRPC Experimental Treatment 1 Intervention

Patients with PSMA-positive mCRPC who have prior treatment with at least one APRI and received taxane chemotherapy (or ineligible/refused); and received a maximum of 3 prior systemic therapy regimens in the mCRPC setting.

Group II: OmHSPC Experimental Treatment 1 Intervention

Patients with prostate cancer and biochemical recurrence after definitive surgery or radiation therapy, with 1-5 PSMA-positive lesions, who have not yet initiated lifelong hormone therapy.

Who Is Running the Clinical Trial?

POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company

Lead Sponsor

Trials

5

Recruited

670+

POINT Biopharma

Lead Sponsor

Trials

6

Recruited

720+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

The LUNAR trial is investigating the efficacy of 177 Lu-PNT2002, a radiolabelled small molecule targeting prostate-specific membrane antigen (PSMA), in combination with stereotactic body radiotherapy (SBRT) for men with oligorecurrent metastatic hormone-sensitive prostate cancer, with 100 patients expected to be enrolled.

This Phase 2 trial aims to determine if adding 177 Lu-PNT2002 to SBRT can improve progression-free survival and other outcomes compared to SBRT alone, potentially offering a new treatment strategy for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LUNAR: a randomized Phase 2 study of 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (clinical trial protocol). Ma, TM., Czernin, J., Felix, C., et al.[2023]

In a study of 13 patients with advanced metastatic castration-resistant prostate cancer (mCRPC), treatment with 225Ac-PSMA targeted alpha-radiation therapy resulted in a median overall survival of 8.5 months, with even better outcomes (12.6 months) for patients who had not previously received PSMA therapy.

Patients experienced significant improvements in quality of life and pain relief, although xerostomia (dry mouth) was a persistent side effect; high baseline PSMA expression and DNA damage repair alterations were identified as potential biomarkers for predicting better survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes and molecular profiling of advanced metastatic castration-resistant prostate cancer patients treated with 225Ac-PSMA-617 targeted alpha-radiation therapy. van der Doelen, MJ., Mehra, N., van Oort, IM., et al.[2022]

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]

The newly designed PSMA-NAT-DA1 (PNT-DA1) shows significantly improved affinity for prostate-specific membrane antigen (PSMA) and higher tumor accumulation compared to the previous PSMA-DA1, indicating enhanced effectiveness for targeting metastatic castration-resistant prostate cancer.

Administration of [225Ac]Ac-PNT-DA1 resulted in tumor shrinkage with minimal toxicity, outperforming existing PSMA-targeting therapies, suggesting that PNT-DA1 could be a superior option for radiotheranostic treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Novel 111In/225Ac-Labeled Agent Targeting PSMA for Highly Efficient Cancer Radiotheranostics. Tsuchihashi, S., Nakashima, K., Tarumizu, Y., et al.[2023]

Radionuclide therapy (RNT) using beta and alpha particles, specifically lutetium-177 (177Lu) and actinium-225 (225Ac) labeled PSMA, shows promise as a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), targeting prostate-specific membrane antigen (PSMA) which is highly expressed in cancer cells.

Clinical studies indicate that these therapies may provide a survival benefit for mCRPC patients, although the field is still developing and further research is needed to fully establish their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in 177Lu-PSMA and 225Ac-PSMA Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer. Ling, SW., de Blois, E., Hooijman, E., et al.[2022]

The new 211At-labeled radiotracer, 211At-3-Lu, effectively targets prostate-specific membrane antigen (PSMA) in prostate cancer cells, showing significant uptake in PSMA+ tumors with minimal uptake in non-target cells, indicating its potential for targeted therapy.

In a long-term toxicity study, 211At-3-Lu demonstrated low off-target toxicity and favorable safety profiles, including stable hematopoietic function and positive histopathological outcomes, suggesting it could be a safe and effective treatment option for patients with prostate cancer resistant to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Improved 211At-Labeled Agent for PSMA-Targeted α-Therapy. Mease, RC., Kang, CM., Kumar, V., 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]

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]

PSMA-targeted thorium-227 conjugate (PSMA-TTC) effectively targets and induces DNA damage in prostate cancer cells, leading to cell death, particularly in cells with high PSMA expression.

In preclinical models, PSMA-TTC demonstrated strong antitumor efficacy, significantly reducing tumor growth and abnormal bone growth associated with metastatic prostate cancer, supporting its potential for clinical evaluation in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer. Hammer, S., Hagemann, UB., Zitzmann-Kolbe, S., et al.[2021]

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]

In a first-in-human trial, two patients with advanced prostate cancer showed a complete response to treatment with 225Ac-PSMA-617, indicating its potential efficacy as a targeted therapy.

The treatment resulted in a significant decline in prostate-specific antigen levels without relevant hematologic toxicity, suggesting a favorable safety profile, with xerostomia being the only notable side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. Kratochwil, C., Bruchertseifer, F., Giesel, FL., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

LUNAR: a randomized Phase 2 study of 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (clinical trial protocol). [2023]

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

Clinical outcomes and molecular profiling of advanced metastatic castration-resistant prostate cancer patients treated with 225Ac-PSMA-617 targeted alpha-radiation therapy. [2022]

3. 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]

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

Development of Novel 111In/225Ac-Labeled Agent Targeting PSMA for Highly Efficient Cancer Radiotheranostics. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Advances in 177Lu-PSMA and 225Ac-PSMA Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer. [2022]

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

An Improved 211At-Labeled Agent for PSMA-Targeted α-Therapy. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

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

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

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer. [2021]

10. 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]

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

225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. [2022]