ACTInium-J591 Radionuclide Therapy in PSMA-Detected Metastatic HOrmone-Sensitive Recurrent Prostate CaNcer

(ACTION Trial)

Overseen By Sharanya Chandrasekhar, M.S.

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: Weill Medical College of Cornell University

Must not be taking: Androgen deprivation, Anti-androgen

Disqualifiers: Metastatic disease, Spinal cord compression, Neuroendocrine features, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on androgen deprivation or anti-androgen therapy to participate.

What data supports the effectiveness of the treatment Actinium-J591, Androgen Deprivation Therapy, Hormone Therapy, ADT, Stereotactic Body Radiation Therapy, Stereotactic Ablative Radiotherapy (SABR), CyberKnife?

Research shows that Actinium-225, a component similar to Actinium-J591, has shown promise in treating metastatic prostate cancer, with higher efficacy and fewer side effects compared to other treatments. This suggests potential effectiveness for Actinium-J591 in similar contexts. ^{1 2 3 4 5}

Is the treatment Actinium-J591 safe for humans?

Research on Actinium-225, a component of Actinium-J591, shows potential for cancer treatment but highlights safety concerns due to radiotoxicity (harmful effects from radiation). In studies with mice, the treatment showed radiotoxicity at certain doses, indicating that safety depends on developing stable forms that can retain harmful byproducts. ^{2 4 6 7 8}

How does the drug Actinium-J591 differ from other treatments for this condition?

Actinium-J591 is unique because it uses actinium-225, a radioactive substance that emits alpha particles, to target and destroy cancer cells. This approach is different from traditional treatments as it delivers radiation directly to the cancer cells, potentially reducing damage to surrounding healthy tissue. ^{2 6 9 10 11}

What is the purpose of this trial?

This trial is testing a new treatment that combines a special drug called Actinium-J591 with either radiation or hormone therapy. It targets patients with prostate cancer that has spread but is not clearly visible on regular scans. The drug helps make the treatments more effective by directly targeting the cancer cells.

Research Team

Himanshu Nagar, M.D.

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

Inclusion Criteria

Pathologically (histologically or cytologically) proven diagnosis of prostate adenocarcinoma at any anatomical location (for example, prostate, metastatic site), including intraductal or ductal carcinoma, at any time before registration

Must meet study entry criteria based on the following diagnostic workup within 120 days prior to enrollment: • History and physical examination 99mTc bone scan (Must be negative or equivocal); Either CT or MRI of pelvis +/- abdomen (Must be negative or equivocal); PSMA PET scan (Must be positive with exception of local disease); Note: All 3 scans are mandatory (bone scan; CT/MR; PET)

To have adequate organ and marrow function, as defined below: a. Absolute neutrophil count (ANC) of ≥2,000/mm3 b. Hemoglobin ≥9 g/dL without need for transfusion c. Platelet count ≥150,000/mm3 and absent history or primary quantitative or qualitative platelet defect d. Serum creatinine of ≤1.5 x ULN or calculated creatinine clearance of ≥60 mL/min/1.73 m2 by Cockcroft-Gault (or determined by 24 hour urine collection) e. Serum total bilirubin ≤1.5 x ULN (unless due to Gilbert's syndrome, in which case direct bilirubin must be normal) f. Serum AST and ALT ≤1.5 x ULN

Exclusion Criteria

Intrapelvic lymph nodes as only site of prostate cancer recurrence

Received a platelet transfusion within 4 weeks of treatment

Biopsy-proven prostatic carcinoma with signet-ring, sarcomatoid, or neuroendocrine features (for example, small cell)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Actinium-J591 combined with radiation therapy or androgen deprivation therapy

3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Actinium-J591
• Androgen Deprivation Therapy
• Stereotactic Body Radiation Therapy

Participant Groups

Group I: Cohort 1 Active Control 2 Interventions

Group II: Cohort 2 Active Control 2 Interventions

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Convergent Therapeutics, Inc.

Collaborator

Trials

1

Findings from Research

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]

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 study found that actinium-225 labeled PSMA-specific tracers ([225Ac]Ac-PSMA-I&T) have a significantly higher relative biological effectiveness (RBE) of 4.2 times compared to lutetium-177 labeled tracers ([177Lu]Lu-PSMA-I&T), suggesting that actinium-225 may provide a more effective treatment for prostate cancer due to its ability to induce more complex DNA damage.

Both tracers showed similar binding characteristics to prostate cancer cells, but [225Ac]Ac-PSMA-I&T resulted in slower DNA double strand break repair kinetics, indicating that the type of radiation emitted by actinium-225 leads to more challenging DNA damage compared to lutetium-177.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T. Ruigrok, EAM., Tamborino, G., de Blois, E., et al.[2022]

Actinium-225 (225Ac) shows promise for tumor-targeted radioimmunotherapy due to its 10-day half-life and ability to emit multiple alpha particles, but complications arise from the release of daughter radioisotopes from the primary chelator.

In experiments with immunocompromised mice, while both the conventional and domain-deleted antibodies effectively delivered 225Ac to tumors, the therapy was limited by radiotoxicity, indicating that safer, stable conjugates are needed for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Actinium-225 conjugates of MAb CC49 and humanized delta CH2CC49. Kennel, SJ., Brechbiel, MW., Milenic, DE., et al.[2013]

The study successfully radiolabeled a DOTA chelate-conjugated peptide with over 95% purity using generator-produced Actinium-225 (225Ac), demonstrating its potential for targeted radiotherapy in cancer treatment.

Using 225Ac/227Ac material for radiolabeling revealed subtle differences in the products, highlighting the need for careful quality control and consideration of processing logistics in the translation of these peptides for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiopharmaceutical Quality Control Considerations for Accelerator-Produced Actinium Therapies. Abou, DS., Zerkel, P., Robben, J., et al.[2023]

References

1. 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]

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

Production of high-purity radium-223 from legacy actinium-beryllium neutron sources. [2019]

3. 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]

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

NorthStar Perspectives for Actinium-225 Production at Commercial Scale. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T. [2022]

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

Preparation of an Actinium-228 Generator. [2020]

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

Actinium-225 conjugates of MAb CC49 and humanized delta CH2CC49. [2013]

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

Computer-Assisted Design of Macrocyclic Chelators for Actinium-225 Radiotherapeutics. [2021]

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

Radiopharmaceutical Quality Control Considerations for Accelerator-Produced Actinium Therapies. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Spectroscopic and computational investigation of actinium coordination chemistry. [2018]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Application of ion exchange and extraction chromatography to the separation of actinium from proton-irradiated thorium metal for analytical purposes. [2018]