Ac-225 Rosopatamab Tetraxetan for Prostate Cancer

Recruiting at 6 trial locations

Overseen By Study Director

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Convergent Therapeutics

Must be taking: ADT, ARSI

Must not be taking: PARP inhibitors, Anticoagulants

Disqualifiers: Superscans, Prior platinum chemotherapy, 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: 5

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a three-part study evaluating the safety and efficacy of a PSMA-directed radioantibody (rosopatamab tetraxetan, conjugated to either In-111 or Ac-225). Part 1 will consist of one administration of In-111-rosopatamab tetraxetan to characterize the biodistribution of the radioantibody to target organs and prostate cancer lesions. Participants then will be enrolled into either Part 2 (Dose Optimization) or Part 3 (Dose Escalation and Expansion) depending on their prior treatment history. Participants qualifying for Part 2 will be randomized to receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle (dose administration on Day 1 and Day 15) at either 45 or 60 kBq/Kg. Participants qualifying for Part 3 must have received prior Lu-177-PSMA-radioligand therapy and will receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle at 45, 55, or 60 kBq/Kg. Dose limiting toxicities (DLTs) will be monitored in Part 3 to determine the recommended phase 2 dose (RP2D), and the study may enroll additional participants to be treated with the RP2D dose level. Participants enrolled into any part will attend study visits which will include blood samples, electrocardiogram (ECG), radiographic imaging, and physical examinations along with other assessments.

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, if you are on anti-coagulants or anti-platelet drugs, you may need to stop if your platelet count drops below a certain level.

What data supports the effectiveness of the drug Ac-225 Rosopatamab Tetraxetan for prostate cancer?

Research shows that treatments using Actinium-225, like Ac-225 Rosopatamab Tetraxetan, have shown promising results in treating metastatic castration-resistant prostate cancer. Actinium-225 is an alpha emitter, which means it can effectively target and kill cancer cells with potentially fewer side effects compared to other treatments. ^{1 2 3 4 5}

Is Ac-225 Rosopatamab Tetraxetan safe for humans?

Ac-225 Rosopatamab Tetraxetan, also known as 225Ac-J591, has been tested in humans for prostate cancer. It is generally well-tolerated, but some patients experienced dry mouth and blood-related side effects like anemia (low red blood cell count). ^{1 3 5 6 7}

What makes Ac-225 Rosopatamab Tetraxetan unique for prostate cancer treatment?

Ac-225 Rosopatamab Tetraxetan is unique because it uses a targeted approach by combining an anti-PSMA antibody with the alpha-emitter actinium-225, specifically targeting prostate cancer cells that overexpress PSMA, potentially offering a more precise and effective treatment for metastatic castration-resistant prostate cancer. ^{1 2 5 8 9}

Eligibility Criteria

This trial is for individuals with PSMA PET-positive castration-resistant prostate cancer. Participants must have a specific type of advanced prostate cancer and may be sorted into different parts of the study based on their previous treatments. Those who've had Lu-177-PSMA therapy go to Part 3, while others may enter Part 2.

Inclusion Criteria

PSMA PET-positive disease with specific criteria

I have previously received Lu-177-PSMA therapy.

My cancer has spread to other parts of my body, confirmed by imaging tests.

Exclusion Criteria

My bone scan shows extensive cancer spread.

I have never taken PARP inhibitors before.

I have received platinum-based chemotherapy before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dosimetry

One administration of In-111-rosopatamab tetraxetan to characterize the biodistribution of the radioantibody to target organs and prostate cancer lesions

1 week

1 visit (in-person)

Dose Optimization

Participants receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle at either 45 or 60 kBq/Kg

2 weeks

2 visits (in-person)

Dose Escalation and Expansion

Participants receive Ac-225 rosopatamab tetraxetan in a single fractionated cycle at 45, 55, or 60 kBq/Kg, with monitoring for dose limiting toxicities

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ac-225 Rosopatamab Tetraxetan

Trial Overview The study tests a radioantibody called rosopatamab tetraxetan, linked to radioactive elements In-111 or Ac-225. It's given in varying doses to see how well it targets cancer cells and what dose is best tolerated. The trial includes initial dosimetry, randomized dose optimization between two levels (55 or 60 KBq/kg), and dose escalation starting at 45 KBq/kg.

Participant Groups

Group I: Part 3: Dose Escalation and Expansion Experimental Treatment 3 Interventions

Participants previously treated with Lu-177-PSMA-radioligand therapy will be assigned to receive one of the three dose levels (45 kBq/kg, 55 kBq/kg, or 60 kBq/kg) depending on the dose limiting toxicities (DLTs) observed.

Group II: Part 2: 60 kBq/kg Ac-225 rosopatamab tetraxetan Experimental Treatment 1 Intervention

Group III: Part 2: 45 kBq/kg Ac-225 rosopatamab tetraxetan Experimental Treatment 1 Intervention

Group IV: Part 1: 148 ± 37 MBq In-111 rosopatamab tetraxetan Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Convergent Therapeutics

Lead Sponsor

Trials

1

Recruited

50+

Findings from Research

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]

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]

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]

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]

The novel radioligand [225Ac]Ac-SibuDAB demonstrated significantly enhanced therapeutic efficacy in treating PSMA-positive tumor xenografts compared to [225Ac]Ac-PSMA-617, requiring only 5 kBq per mouse to eradicate tumors, while [225Ac]Ac-PSMA-617 led to tumor regrowth in treated mice.

[225Ac]Ac-SibuDAB showed improved blood retention and binding to serum albumin, which may contribute to its effectiveness, and was well tolerated at a dose of 30 kBq per mouse, indicating a favorable safety profile for targeted α-therapy in prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617. Busslinger, SD., Tschan, VJ., Richard, OK., 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]

In a meta-analysis of 263 patients with metastatic castration-resistant prostate cancer (mCRPC), 225Ac-PSMA radioligand therapy (RLT) resulted in over 60% of patients experiencing more than a 50% decline in prostate-specific antigen (PSA) levels, indicating significant therapeutic efficacy.

While 225Ac-PSMA RLT showed promising results, common adverse effects included xerostomia (dry mouth) in about 63% of patients and severe hematotoxicity (anemia, leukocytopenia, and thrombocytopenia) in 4% to 14% of patients, highlighting the need for monitoring side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of 225Ac-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis. Lee, DY., Kim, YI.[2022]

Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO™) is a targeted radioligand therapy approved in the USA for treating metastatic castration-resistant prostate cancer (mCRPC) that expresses prostate-specific membrane antigen (PSMA), based on positive results from the phase 3 VISION trial.

This therapy specifically targets PSMA, which is overexpressed in prostate cancer cells, allowing for a more effective treatment option for patients who have already undergone other therapies like androgen receptor inhibition and taxane-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lutetium Lu 177 Vipivotide Tetraxetan: First Approval. Keam, SJ.[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]

References

1. 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]

2. 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]

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

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

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

[225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Effects of 225Ac-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Lutetium Lu 177 Vipivotide Tetraxetan: First Approval. [2022]

9. 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]