Targeted Alpha-Particle Therapy for Melanoma

Recruiting at 12 trial locations

Overseen By Michael A McDonald, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Perspective Therapeutics

Must not be taking: Corticosteroids, Immunosuppressants, Herbal supplements, others

Disqualifiers: Active secondary malignancy, Autoimmune disease, Hepatitis, 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: Unknown

264 Participants Needed

Trial Summary

What is the purpose of this trial?

In this first-in human, phase I/IIa study, the safety and efficacy of \[212Pb\]VMT01, an alpha-particle emitting therapeutic agent targeted to melanocortin sub-type 1 receptor (MC1R) is being evaluated as a monotherapy and in combination with Nivolumab in subjects with unresectable and metastatic melanoma.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for those on prior intravenous or oral therapies. You must stop intravenous therapies for 21 days and oral therapies for 7 days before starting the trial treatment.

What data supports the effectiveness of the treatment [212Pb]VMT01, VMT01 for melanoma?

Research shows that targeted alpha-particle therapy, like [212Pb]VMT01, can effectively target and kill melanoma cells by delivering high-energy radiation directly to the cancer cells. Similar treatments have shown promising results in delaying tumor growth and improving survival in melanoma models, suggesting potential effectiveness for this treatment. ^{1 2 3 4 5}

Is targeted alpha-particle therapy generally safe for humans?

In a Phase I trial of targeted alpha-particle therapy for metastatic melanoma, no adverse events were reported, indicating it was generally safe for humans. However, a slight decrease in platelets was observed in another study, but no toxicity was found in red blood cells, bone marrow, liver, or kidney. ^{1 2 3 4 5}

How is the drug [212Pb]VMT01 different from other melanoma treatments?

The drug [212Pb]VMT01 is unique because it uses targeted alpha-particle therapy, which delivers high-energy radiation directly to cancer cells, causing irreparable damage while minimizing harm to surrounding healthy tissue. This approach is particularly effective for killing single cancer cells and overcoming resistance seen in other treatments. ^{1 2 5 6 7}

Eligibility Criteria

Adults over 18 with advanced melanoma that's spread or can't be removed by surgery, who've had at least one prior treatment fail. They must have a tumor visible on specific scans, be able to lie still for imaging, and not be pregnant or breastfeeding. Men and women must agree to use effective contraception.

Inclusion Criteria

My organs are functioning well.

I have completed a wash-out period after my last cancer treatment before starting [212Pb]VMT01.

You are expected to live for at least 3 more months.

Exclusion Criteria

Treatment with another investigational drug product (therapeutic IND agents) within the last 30 days

I do not require immediate treatment for brain metastasis.

Existence of any medical or social issues likely to interfere with study conductor that may cause increased risk to the subject or to others, e.g., lack of ability to follow radiation safety precautions

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Dose-Escalation

[212Pb]VMT01 is administered alone in escalating doses to determine the Maximum Tolerated Dose (MTD), Maximum Feasible Dose (MFD), and potential recommended Phase 2 doses (RP2Ds)

Approximately 8 weeks per dose, up to 3 doses

Combination-Therapy Dose-Escalation

[212Pb]VMT01 and Nivolumab are administered in escalating doses to determine MTD, MFD, and RP2Ds

Approximately 8 weeks per dose, up to 3 doses

Dose Expansion

Subjects are enrolled in monotherapy and combination-therapy expansion cohorts based on the identified MTD, MFD, and RP2D for further clinical development

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• [212Pb]VMT01

Trial Overview [212Pb]VMT01 is being tested for safety and effectiveness in treating advanced melanoma. It's an alpha-particle therapy targeting MC1R receptors on cancer cells. This trial will include patients whose tumors absorb a related compound seen in special imaging tests.

Participant Groups

Group I: Monotherapy-Dose Escalation Experimental Treatment 2 Interventions

Enrolled subjects will be treated with increasing doses of \[212Pb\]VMT01 (up to 15 mCi) to determine MTD, MFD, and RP2D. Up to 32 subjects will be enrolled. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Monotherapy Dose-Escalation arm.

Group II: Monotherapy - Dose Expansion Experimental Treatment 2 Interventions

Up to 2 monotherapy expansion cohorts of up to 25 subjects will be enrolled at previously identified RP2D to confirm the RP2D and regimen for the Phase 2 dose-expansion cohort. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Monotherapy-Dose Expansion.

Group III: Combination Therapy-Dose Escalation Experimental Treatment 3 Interventions

Enrolled subjects will be treated with increasing radioactive doses of \[212Pb\]VMT01 (up to 15 mCi) in combination with nivolumab to determine MTD, MFD, and RP2D. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Combination Therapy-Dose Escalation.

Group IV: Combination Therapy - Dose Expansion Experimental Treatment 3 Interventions

Up to 2 Combination Therapy expansion cohorts of up to 25 subjects will be enrolled at RP2Ds previously identified to confirm the RP2D and regimen for the Phase 2 dose-expansion cohort. A dosimetry sub-study utilizing \[203Pb\]VMT01 has been incorporated into Combination Therapy-Dose Expansion. Once the RP2D and regimen for the Phase 2 dose-expansion cohort is confirmed, up to 100 subjects will be enrolled to confirm the efficacy and safety of the RP2D and regimen.

[212Pb]VMT01 is already approved in United States for the following indications:

Approved in United States as VMT01 for:

• Unresectable and metastatic melanoma

Who Is Running the Clinical Trial?

Perspective Therapeutics

Lead Sponsor

Trials

6

Recruited

710+

Viewpoint Molecular Targeting

Lead Sponsor

Trials

4

Recruited

570+

Findings from Research

Targeted alpha-particle therapy (TAT) using a 213Bi-anti-human-PD-L1 monoclonal antibody significantly delayed tumor growth and improved survival in a human melanoma xenograft model, indicating its potential as an effective treatment for melanoma.

The treatment showed specific targeting of PD-L1 positive tumors with minimal toxicity, as it did not harm red blood cells, bone marrow, liver, or kidney, although a slight decrease in platelets was noted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Tumor Efficacy of PD-L1 Targeted Alpha-Particle Therapy in a Human Melanoma Xenograft Model. Capitao, M., Perrin, J., Simon, S., et al.[2021]

Targeted alpha-particle therapy (TAT) offers a promising approach for cancer treatment due to its high potency and specificity, allowing for the effective killing of individual cancer cells through self-irradiation.

Clinical trials using various radionuclides, such as (213)Bi and (223)Ra, have demonstrated the therapeutic advantages of TAT, particularly in treating castration-resistant prostate cancer, although challenges like limited radionuclide availability remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potential and hurdles of targeted alpha therapy - clinical trials and beyond. Elgqvist, J., Frost, S., Pouget, JP., et al.[2022]

Targeted alpha particle therapy (TAT) offers significant therapeutic advantages due to the short and highly ionizing path of alpha particles, which can enhance the efficacy of cancer treatment compared to traditional radiotherapy.

The review highlights ongoing and completed clinical trials, indicating that TAT is a promising area of research with potential for future developments in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications. Nelson, BJB., Andersson, JD., Wuest, F.[2021]

In a Phase I study involving 38 patients with stage IV metastatic melanoma, targeted α-therapy using the α-immunoconjugate (213)Bi-cDTPA-9.2.27 showed a 10% objective partial response rate and 40% stable disease at 8 weeks, indicating some effectiveness in managing advanced melanoma.

The treatment was well-tolerated with no adverse events reported, and the median survival for patients was 8.9 months, suggesting that this experimental therapy may provide a new avenue for treatment without significant toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of patient survival in a Phase I trial of systemic targeted α-therapy for metastatic melanoma. Allen, BJ., Singla, AA., Rizvi, SM., et al.[2022]

The study evaluated a melanoma-targeting peptide conjugated with an alpha-particle-emitting radionuclide in a mouse model, showing that this treatment significantly extended survival times in melanoma-bearing mice, with some achieving complete remission.

Mice treated with the highest dose of the radionuclide (200 muCi) had a mean survival of 49.8 days compared to 14.6 days for the placebo group, indicating the potential efficacy of this targeted therapy in overcoming radiation resistance in tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanoma therapy via peptide-targeted {alpha}-radiation. Miao, Y., Hylarides, M., Fisher, DR., et al.[2010]

α-Particle irradiation is gaining recognition as a powerful treatment for cancer, with unique properties that enhance its effectiveness in targeted therapy.

Clinical studies have shown that α-particle emitters are safe and effective for treating conditions like leukemia and metastatic cancer, highlighting their potential as tumor-selective therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted and Nontargeted α-Particle Therapies. McDevitt, MR., Sgouros, G., Sofou, S.[2020]

Targeted alpha-particle therapy using monoclonal antibodies to deliver radioisotopes directly to tumor cells shows promise for more effective tumor cell killing while minimizing damage to surrounding healthy tissues, making it suitable for treating minimal residual disease.

Clinical trials have confirmed the safety and feasibility of this therapy, but further research is needed to explore more potent isotopes and improve delivery methods to establish its clinical effectiveness compared to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promise of targeted {alpha}-particle therapy. Mulford, DA., Scheinberg, DA., Jurcic, JG.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-Tumor Efficacy of PD-L1 Targeted Alpha-Particle Therapy in a Human Melanoma Xenograft Model. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

The potential and hurdles of targeted alpha therapy - clinical trials and beyond. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Analysis of patient survival in a Phase I trial of systemic targeted α-therapy for metastatic melanoma. [2022]

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

Melanoma therapy via peptide-targeted {alpha}-radiation. [2010]

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

Targeted and Nontargeted α-Particle Therapies. [2020]

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

The promise of targeted {alpha}-particle therapy. [2022]