Alpha Particle Radiotherapy for Eye Cancer

Overseen By Karen E Hayes, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Modulation Therapeutics, Inc.

Must not be taking: Anticancer, Antivirals, Corticosteroids

Disqualifiers: CNS metastases, Active malignancy, Pregnancy, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 day

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called 225Ac-MTI-201, an alpha particle radiotherapy, for individuals with metastatic uveal melanoma, a type of eye cancer that has spread. The main goal is to determine the highest dose that can be safely administered. Researchers are also examining how the body processes the drug and any potential side effects. The trial seeks participants with confirmed metastatic uveal melanoma who have tried at least one prior treatment without success. 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 therapy.

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.

Is there any evidence suggesting that 225Ac-MTI-201 is likely to be safe for humans?

Research has shown that 225Ac-MTI-201 could be a promising treatment for eye cancer. This treatment uses Actinium-225 to deliver radiation directly to cancer cells with precision, potentially protecting healthy cells from damage.

However, the treatment remains in the early stages, and researchers are determining the safest dose. As a result, information about its safety in humans is limited. Participants in earlier studies have tolerated this type of radiation treatment well. Nonetheless, like any new treatment, side effects may occur, and researchers are studying these carefully.

As a new and experimental treatment, understanding its safety fully will require more time and research. Participants in these studies help scientists gather crucial data to determine the safest way to use 225Ac-MTI-201. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for eye cancer?

Unlike the standard treatments for eye cancer, which often include surgery, radiation therapy, and chemotherapy, 225Ac-MTI-201 introduces a new approach with alpha particle radiotherapy. This treatment uses a radioactive isotope, Actinium-225, which delivers high-energy alpha particles directly to cancer cells, minimizing damage to surrounding healthy tissue. Researchers are excited because this targeted method could lead to fewer side effects and potentially more effective results in destroying cancer cells compared to traditional methods.

What evidence suggests that 225Ac-MTI-201 might be an effective treatment for metastatic uveal melanoma?

Research shows that 225Ac-MTI-201, administered in varying doses to trial participants, could be a promising treatment for metastatic uveal melanoma, a type of eye cancer. This drug uses Actinium-225, which releases tiny particles to deliver powerful and precise radiation directly to cancer cells. Early human studies have shown that 225Ac-MTI-201 is stable and specifically targets a protein called MC1R, found on melanoma cells, to destroy them. Initial results suggest it can effectively kill cancer cells without causing significant harm to healthy tissue. While more research is needed, these findings offer hope that 225Ac-MTI-201 could become a treatment option for this difficult-to-treat cancer. ^{1 2 3 4 6}

Who Is on the Research Team?

Nikhil Khushalani, MD

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Mark L McLaughlin

Principal Investigator

Modulation Therapeutics, Inc.

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• 225Ac-MTI-201

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.

How Is the Trial Designed?

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.

225Ac-MTI-201 is already approved in United States for the following indications:

Approved in United States as 225Ac-MTI-201 for:

• Metastatic uveal melanoma

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. asco.org asco.org/abstracts-presentations/ABSTRACT464540

First-in-human study of 225actinium mti-201 (225Ac- ... We developed a novel MC1R targeted radiopharmaceutical 225Ac-MTI-201, and demonstrated high biostability, affinity, MC1R-specific cytotoxicity with defined ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11979469/

How we treat patients with metastatic uveal melanoma - PMC Tebentafusp, a T-cell receptor-based molecule, is the first US Food and Drug Administration/European Medicines Agency-approved systemic therapy ...

3. withpower.com withpower.com/trial/phase-1-melanoma-6-2022-af3ca

Alpha Particle Radiotherapy for 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 ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-06812

Targeted Alpha Particle Radiotherapy for Metastatic Uveal ... The primary aim of the study is to establish the maximum-tolerated dose (MTD) of 225Ac-MTI-201 in participants with metastatic uveal melanoma.

5. delta.larvol.com delta.larvol.com/Products/?ProductId=94ca5dda-53a1-4f8e-8e0a-81f5660ff200

MTI-201 / Modulation Therap Preliminary results of first-in-human study of 225-Actinium MTI-201 (225Ac-MTI-201) in metastatic uveal melanoma (ESMO 2024) - P1 | "In early assessment, ...

6. malacards.org malacards.org/card/ocular_melanoma

Ocular Melanoma Integrated disease information for Ocular Melanoma including associated genes, mutations, phenotypes, pathways, drugs, and more - integrated from 78 data ...