Alpha Particle Radiotherapy for Eye Cancer

Overseen by Nikhil Khushalani, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Modulation Therapeutics, Inc.

Must not be taking: Anticancer, Antivirals, Corticosteroids

Disqualifiers: CNS metastases, Active malignancy, Pregnancy, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug in patients with a specific type of eye cancer that has spread and hasn't responded to other treatments. The drug uses a radioactive substance to kill cancer cells.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the treatment 225Ac-MTI-201 for eye cancer?

Research shows that Actinium-225, used in similar treatments, can effectively target and kill cancer cells with minimal damage to surrounding healthy tissue. This is due to its ability to emit alpha particles that cause significant damage to cancer cells, making it a promising option for treating various types of cancer. ^{1 2 3 4 5}

Is Actinium-225 radiotherapy generally safe for humans?

Actinium-225 radiotherapy has shown potential in targeting cancer cells with minimal impact on normal tissue, but there are concerns about the radiotoxicity (harmful effects of radiation) of its decay products. Studies in mice have shown that the treatment can be effective, but the safety in humans depends on developing stable compounds that can retain these decay products to minimize harm. ^{1 2 6 7 8}

What makes the drug 225Ac-MTI-201 unique for treating eye cancer?

The drug 225Ac-MTI-201 is unique because it uses Actinium-225, an alpha particle-emitting isotope, which delivers highly targeted and potent radiation to cancer cells with minimal damage to surrounding healthy tissue, making it a promising option for treating eye cancer. ^{1 3 7 9 10}

Research Team

Nikhil Khushalani, MD

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Mark L McLaughlin

Principal Investigator

Modulation Therapeutics, Inc.

Eligibility Criteria

Adults with metastatic uveal melanoma who've had at least one prior treatment can join. They must have good performance status, measurable disease, and proper organ/marrow function. Participants need to use two forms of contraception if applicable and sign consent. Excluded are pregnant/nursing women, those with uncontrolled illnesses or certain other cancers, prior alpha-particle therapy recipients, and individuals with symptomatic brain metastases or significant immunocompromise.

Inclusion Criteria

My blood tests show normal organ function.

I agree to use two forms of birth control during and up to 3 months after treatment.

My uveal melanoma has worsened after at least one treatment.

Exclusion Criteria

I have previously received alpha-particle therapy.

I do not have any severe illnesses or social situations that would stop me from following the study's requirements.

I am not pregnant or nursing, and if capable of childbearing, I have a recent negative pregnancy test.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravenous dose of 225Ac-MTI-201 with dose escalation based on safety assessments

1 day

1 visit (in-person, overnight stay)

Initial Follow-up

Participants are monitored for safety and effectiveness with weekly clinic visits for the first month and a visit on Week 9

9 weeks

Weekly visits (in-person) for the first month, 1 visit on Week 9

Long-term Follow-up

Participants undergo tumor measurements and health assessments every 8 weeks in the first year, extended to 12 weeks in year 2, 16 weeks in year 3, and 24 weeks in years 4 and 5

Up to 3 years

Regular visits (in-person) with decreasing frequency over time

Treatment Details

Interventions

• 225Ac-MTI-201 (Radiopharmaceutical)

Trial Overview The trial is testing different doses of a radiotherapy drug called 225Ac-MTI-201 to find the highest dose patients can tolerate without severe side effects (MTD). It also looks at how the body processes the drug and its toxic effects in those with metastatic uveal melanoma.

Participant Groups

Group I: 225Ac-MTI-201 998 microCi Experimental Treatment 1 Intervention

Cohort 11: Participants were administered a single dose of 998 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group II: 225Ac-MTI-201 9.5 microCi Experimental Treatment 1 Intervention

Cohort 2: Participants were administered a single dose of 9.5 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group III: 225Ac-MTI-201 76 microCi Experimental Treatment 1 Intervention

Cohort 5: Participants were administered a single dose of 76 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group IV: 225Ac-MTI-201 750 microCi Experimental Treatment 1 Intervention

Cohort 10: Participants were administered a single dose of 750 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group V: 225Ac-MTI-201 564 microCi Experimental Treatment 1 Intervention

Cohort 9: Participants were administered a single dose of 564 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group VI: 225Ac-MTI-201 424 microCi Experimental Treatment 1 Intervention

Cohort 8: Participants were administered a single dose of 424 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group VII: 225Ac-MTI-201 4.7 microCi Experimental Treatment 1 Intervention

Cohort 1: Participants were administered a single dose of 4.7 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group VIII: 225Ac-MTI-201 38 microCi Experimental Treatment 1 Intervention

Cohort 4: Participants were administered a single dose of 38 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group IX: 225Ac-MTI-201 254 microCi Experimental Treatment 1 Intervention

Cohort 7: Participants were administered a single dose of 254 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group X: 225Ac-MTI-201 19 microCi Experimental Treatment 1 Intervention

Cohort 3: Participants were administered a single dose of 19 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group XI: 225Ac-MTI-201 152 microCi Experimental Treatment 1 Intervention

Cohort 6: Participants were administered a single dose of 152 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Group XII: 225Ac-MTI-201 1327 microCi Experimental Treatment 1 Intervention

Cohort 12: Participants were administered a single dose of 1327 microCi of 225Ac-MTI-201 via intravenous catheter, with up to 3 years of follow-up.

Who Is Running the Clinical Trial?

Modulation Therapeutics, Inc.

Lead Sponsor

Trials

1

Recruited

20+

H. Lee Moffitt Cancer Center and Research Institute

Collaborator

Trials

576

Recruited

145,000+

Patrick Hwu

H. Lee Moffitt Cancer Center and Research Institute

Chief Executive Officer since 2020

MD from The Medical College of Pennsylvania

Wade J. Sexton

H. Lee Moffitt Cancer Center and Research Institute

Chief Medical Officer

MD

Findings from Research

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]

The study introduces a novel alpha-particle emitting radioembolization treatment using [225Ac]Ac-DOTA-TDA, which effectively targets liver tumors while minimizing damage to normal tissue, showing significant improvements in overall survival in mouse models.

SPECT imaging successfully monitored the distribution of the treatment agent and its decay products, providing a promising method for tracking the effectiveness of Actinium-225 labeled therapies in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary evaluation of alpha-emitting radioembolization in animal models of hepatocellular carcinoma. Du, Y., Cortez, A., Josefsson, A., et al.[2022]

Alpha particle-emitting isotopes like Actinium-225 (225 Ac) show promise as targeted cancer therapies due to their ability to deliver dense radiation damage to tumor cells while minimizing harm to surrounding healthy tissue.

225 Ac acts as an alpha particle nanogenerator, producing multiple alpha particles during its decay, which enhances its potential effectiveness in specifically targeting and destroying cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha particle therapy applications. Miederer, M., Scheinberg, DA., McDevitt, MR.[2021]

Actinium-225 labeled DOTATOC is significantly more effective than Lutetium-177 labeled DOTATOC in inducing cell death in tumor cells, requiring much lower doses to achieve similar biological effects, as shown by the ED50 values of 14 kBq/ml for Ac-225 compared to 10 MBq/ml for Lu-177.

The formation of γH2AX-foci, which indicates DNA double strand breaks, was higher in tumors treated with Ac-225-DOTATOC, suggesting that alpha-particle therapy may lead to more effective tumor control compared to beta-particle therapy, as evidenced by the greater number of cells with γH2AX-foci in Ac-225 treated tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy. Graf, F., Fahrer, J., Maus, S., et al.[2021]

α-particle targeted radionuclide therapy, particularly using Actinium-225 (225Ac), shows great potential for cancer treatment due to its ability to deliver high-energy radiation that specifically targets tumors while minimizing damage to surrounding healthy tissues.

Despite its advantages, challenges such as source availability and inconsistent treatment outcomes due to current dosimetry modeling need to be addressed to optimize the use of 225Ac in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Actinium-225 Targeted Agents: Where Are We Now? Mourtada, F., Tomiyoshi, K., Sims-Mourtada, J., et al.[2023]

The alpha-emitting radioimmunotherapy [225Ac]Ac-DOTA-C595 effectively targets pancreatic ductal adenocarcinoma (PDAC) cells that express the MUC1-CE marker, leading to significant DNA damage in over 99% of these cells within one hour of exposure.

In vitro studies demonstrated that [225Ac]Ac-DOTA-C595 exhibits concentration-dependent cytotoxicity, with stronger effects on cells with high MUC1-CE expression, suggesting its potential as a targeted treatment for PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of [225Ac]Ac-DOTA-C595 as radioimmunotherapy of pancreatic cancer: in vitro evaluation, dosimetric assessment and detector calibration. Hull, A., Hsieh, W., Borysenko, A., et al.[2023]

Actinium-225 is being used in clinical settings for treating acute myelogenous leukemia, showcasing its effectiveness as a targeted radioimmunotherapy due to its high cytotoxicity against cancer cells while sparing normal tissues.

The unique properties of Actinium-225, including its short tissue range, high energy transfer, and optimal half-life, make it a promising candidate for targeted cancer therapies, potentially enhancing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Actinium-225 in targeted alpha-particle therapeutic applications. Scheinberg, DA., McDevitt, MR.[2021]

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]

Radium-223 dichloride (223RaCl2) has been shown to improve overall survival in prostate cancer patients with bone metastases, marking a significant advancement in treatment options.

This success with 223RaCl2 has sparked renewed interest in developing targeted alpha-particle therapies for treating both bone and visceral metastases, highlighting a potential shift in therapeutic strategies for metastatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress in Targeted Alpha-Particle-Emitting Radiopharmaceuticals as Treatments for Prostate Cancer Patients with Bone Metastases. Patel, CM., Wadas, TJ., Shiozawa, Y.[2023]

Proton beam radiation doses between 6-8 cobalt gray equivalent effectively inhibit choroidal endothelial cells while preserving retinal ganglion and retinal pigment epithelial cells, indicating a safe therapeutic window for treating choroidal neovascularization in age-related macular degeneration (AMD).

Significant increases in reactive oxygen species levels were observed in choroidal endothelial cells exposed to radiation, suggesting that this mechanism may contribute to the cell viability decline at higher radiation doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential sensitivity of choroidal endothelial, retinal ganglion, and retinal pigment epithelial cells in vitro to proton radiation. Balaiya, S., Murthy, RK., Malyapa, R., et al.[2018]

References

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

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

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

Preliminary evaluation of alpha-emitting radioembolization in animal models of hepatocellular carcinoma. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha particle therapy applications. [2021]

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

DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy. [2021]

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

Actinium-225 Targeted Agents: Where Are We Now? [2023]

6. England pubmed.ncbi.nlm.nih.gov

Development of [225Ac]Ac-DOTA-C595 as radioimmunotherapy of pancreatic cancer: in vitro evaluation, dosimetric assessment and detector calibration. [2023]

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

Actinium-225 in targeted alpha-particle therapeutic applications. [2021]

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

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

Progress in Targeted Alpha-Particle-Emitting Radiopharmaceuticals as Treatments for Prostate Cancer Patients with Bone Metastases. [2023]

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

Differential sensitivity of choroidal endothelial, retinal ganglion, and retinal pigment epithelial cells in vitro to proton radiation. [2018]