Actinium-J591 for 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the safety of combining Actinium-J591, an experimental treatment, with radiation or hormone therapy for prostate cancer that has spread but remains sensitive to hormone treatment. It targets individuals diagnosed with prostate cancer that may have recurred but who have not yet received treatments like chemotherapy. Participants must have a positive result on a specific prostate cancer scan (PSMA PET) and meet other health criteria. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Actinium-J591 has undergone safety testing in earlier studies. One study examined patient reactions to various doses of Actinium-J591 and found it to be relatively safe. The goal was to identify the highest dose tolerable without serious side effects. Researchers also tested Actinium-J591 in patients who had previously tried other treatments. Results from these trials indicated that the treatment was generally well-tolerated, with manageable side effects. Although Actinium-J591 remains under study, these early findings suggest it may be safe for use in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Actinium-J591 because it offers a novel approach to treating metastatic hormone-sensitive recurrent prostate cancer. Unlike traditional treatments such as androgen deprivation therapy or chemotherapy, Actinium-J591 uses a targeted radionuclide therapy that specifically seeks out and binds to PSMA (Prostate-Specific Membrane Antigen) on cancer cells. This targeted delivery allows for a more precise attack on cancer cells while sparing healthy tissue, potentially reducing side effects and improving patient outcomes. By utilizing this innovative mechanism, Actinium-J591 could provide a more effective and tolerable treatment option for patients battling this form of prostate cancer.

What evidence suggests that this trial's treatments could be effective?

Research shows that Actinium-J591, which participants in this trial may receive, has promising results for treating prostate cancer. In earlier studies, patients experienced a decrease in prostate-specific antigen (PSA) levels, indicating that the treatment might be reducing the cancer. One study found that 79% of patients showed some improvement in cancer cells in their blood, suggesting the treatment's potential to effectively target cancer cells. Additionally, 225Ac-J591 demonstrated a 71% response rate in organ tumors and a 52% response rate in bone tumors. These findings suggest that Actinium-J591 could be a helpful option for managing advanced prostate cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Himanshu Nagar, M.D.

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

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

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37922438/

A Phase I Dose-Escalation Study of 225Ac-J591 - PubMed - NIH This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, ...

2. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.23.00573

A Phase I Dose-Escalation Study of 225Ac-J591 Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: ...

3. urotoday.com urotoday.com/conference-highlights/aua-2025/aua-2025-prostate-cancer/160076-aua-2025-psma-targeted-actinium-225-therapy-in-metastatic-castration-resistant-prostate-cancer-comparative-outcomes-between-monotherapy-vs-combination-therapy.html

AUA 2025: PSMA-Targeted Actinium-225 Therapy in ... Ac-J591 combination therapy demonstrated a higher PSA50 response rate compared to monotherapy (57% versus 48%), albeit not statistically ...

4. ecancer.org ecancer.org/en/video/11199-a-single-fractionated-cycle-of-225ac-j591-shows-preliminary-efficacy-on-mcrpc-patients

A single fractionated cycle of 225Ac-J591 shows ... Of 14 patients evaluable at baseline at 12 weeks for CTC counts, or circulating tumour cell counts, we saw responses of any type in 79% of ...

5. cancertherapyadvisor.com cancertherapyadvisor.com/reports/225ac-j591-yields-responses-in-difficult-to-treat-metastatic-prostate-cancer/

225Ac-J591 Yields Responses in Difficult-to-Treat ... The rate of molecular response was 71% in visceral lesions (9% complete response rate), 52% in bone lesions (7% complete response rate), and 39% ...

6. jnm.snmjournals.org jnm.snmjournals.org/content/65/supplement_2/241342

Actinium (Ac-225) Rosopatamab tetraxetan (Ac-RT) therapy in ... Administration of two doses of 55-65 KBq/kg (injected 2 weeks apart) of Ac-RT is relatively safe for the treatment of mCRPC.

7. urotoday.com urotoday.com/video-lectures/aua-2025/video/4861-actinium-psma-j591-after-prior-lutetium-therapy-in-metastatic-prostate-cancer-scott-tagawa.html

Actinium-PSMA J591 After Prior Lutetium Therapy in ... Dr. Tagawa presents post-hoc analysis from three prospective trials examining 37 patients who received actinium J591, a potent alpha-emitter targeting PSMA's ...

8. convergentrx.com convergentrx.com/prostate-cancer/

Prostate Cancer Learn about CONV01-α (formerly Ac-225-J591), which is an alpha-emitting radioantibody with a promising clinical future in mCRPC.