Targeted alpha-particle therapy for advanced melanoma

A Phase I/IIa, First-In-Human, Multi-Center, Monotherapy and Combination-Therapy With Nivolumab, Dose-Finding and Dose-Expansion Study of [212Pb]VMT01 Melanocortin-1 Receptor-Targeted, Image-Guided Alpha-Particle Therapy in Subjects With Previously Treated Unresectable or Metastatic Melanoma

This study is testing a new treatment for advanced melanoma that uses targeted radiation to see if it can help patients whose cancer can't be surgically removed.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 300 (estimated)
• Ages: 18 Years to 90 Years
• Sex: All
• Sponsor: Perspective Therapeutics (Industry-sponsored)
• Drugs / interventions: nivolumab, chemotherapy, radiation, prednisone
• Locations: 13 sites (Orange, California and 12 other locations)
• Trial ID: NCT05655312 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety and efficacy of a novel alpha-particle emitting therapeutic agent, [212Pb]VMT01, which targets the melanocortin sub-type 1 receptor (MC1R) in patients with unresectable and metastatic melanoma. The study is structured in three parts: a monotherapy dose-escalation phase to determine the maximum tolerated dose, a combination therapy phase with Nivolumab, and a dose expansion phase for further clinical development. Up to 264 subjects with confirmed melanoma and positive MC1R imaging will be enrolled to assess the therapeutic potential of this targeted approach.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with unresectable Stage III or IV metastatic melanoma who have previously progressed on at least one approved first-line therapy.

Not a fit: Patients with resectable melanoma or those who have not progressed on first-line therapies may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new targeted therapy option for patients with advanced melanoma, potentially improving outcomes and survival rates.

How similar studies have performed: Other studies have shown promise with targeted alpha-particle therapies, but this specific approach is novel and represents an untested combination.

Eligibility criteria

Inclusion Criteria:

* Ability to understand and willingness to provide informed consent, willingness to comply with all study procedures for the duration of the study
* Aged ≥ 18 years
* Diagnosed with unresectable Stage III or Stage IV metastatic or recurrent melanoma
* Previously progressed (radiological progression) on at least one approved systemic therapy for advanced melanoma
* Uptake of \[68Ga\]VMT02 or \[203Pb\]VMT01 by PET or SPECT imaging observed in at least one melanoma tumor site using quantitative imaging analysis compared to reference normal tissue
* Subjects on prior intravenous therapy (e.g., chemotherapy or checkpoint inhibitors), or prior oral therapy (e.g.,proto-oncogene B-RAF or mitogen-activated extracellular signal-regulated kinase inhibitors) who demonstrate MC1R positivity during screening are eligible for enrollment, provided that they undergo a wash-out period of 21 days, or 7 days, respectively, prior to Cycle 1 Day 1 treatment with \[212Pb\]VMT01.
* Presence of measurable disease by RECIST v1.1 assessed within 45 days prior to the first dose of \[212Pb\]VMT01 on Cycle 1 Day 1
* Ability to lie flat and still for up to two hours for imaging scans; moderate conscious sedation allowed if indicated
* For females of reproductive potential: agree to use of highly effective contraception and refrain from donating eggs (ova, oocytes) for the purpose of reproduction starting from screening, during treatment with \[212Pb\]VMT01 and/or nivolumab, and for at least 6 months after the last dose of \[212Pb\]VMT01 and/or nivolumab, whichever is administered last
* For males of reproductive potential: agree to use of condoms or other methods to ensure effective contraception and refrain from donating sperm starting from screening, during treatment with \[212Pb\]VMT01 and/or nivolumab, and for at least 6 months after the last dose of \[212Pb\]VMT01 and/or nivolumab, whichever is administered last
* Eastern Cooperative Oncology Group performance score of \< 2 at Screening
* Life expectancy of at least 3 months after Cycle 1 Day 1
* Satisfactory organ function determined by laboratory testing

Exclusion Criteria:

* Active secondary malignancy
* Prior systematic treatment with radioactive nuclides. Subjects who had localized treatment with radioactive nuclides or imaging using radioactive imaging agents may be enrolled
* Pregnancy or breastfeeding a child
* Any serious/active/uncontrolled infection requiring parenteral antibiotics within 2 weeks before the first administration of \[212Pb\]VMT01
* Febrile illness within 48 hours of any scheduled investigational product (\[212Pb\]VMT01, \[203Pb\]VMT01, or \[68Ga\]VMT02) administration; subjects should be rescheduled \> 48 hours after resolution of fever
* Treatment with another investigational drug product (therapeutic IND agents) within the last 45 days before the first dose of \[212Pb\]VMT01 on C1D1.
* Current abuse of alcohol or illicit drugs
* 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

Additional exclusion criteria for subjects who will receive combination therapy with nivolumab:

* Untreated central nervous system (CNS) metastasis or metastasis requiring acute therapy of any modality. Subjects must have been either off corticosteroids, or on a stable or decreasing dose of prednisone (or equivalent) for at least 2 weeks prior to the first dose of \[212Pb\]VMT01
* Subjects with an active, known, or suspected autoimmune disease
* Subjects with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications
* Acute or chronic hepatitis B (e.g., Hepatitis B surface antigen reactive), hepatitis C (e.g., HCV RNA \[qualitative\] is detected) or known history of Human Immunodeficiency Virus (HIV) with an acquired immunodeficiency syndrome
* Treatment with complementary medications (e.g., herbal supplements or traditional Chinese medicines)
* Existence of abnormal laboratory values in hematology, liver, and renal function
* Treatment with any live/attenuated vaccine within 30 days prior to the first dose of \[212Pb\]VMT01
* Any treatment-related toxicities from prior systemic immune therapy with the exception of those unlikely to re-occur with standard countermeasures
* History of allergy or hypersensitivity to nivolumab or its components

Where this trial is running

Orange, California and 12 other locations

• University of California Irvine — Orange, California, United States (Recruiting)
• Mayo Clinic — Jacksonville, Florida, United States (Recruiting)
• University of Miami — Miami, Florida, United States (Recruiting)
• Sarasota Memorial Hospital — Sarasota, Florida, United States (Recruiting)
• University of Iowa — Iowa City, Iowa, United States (Recruiting)
• University of Kentucky — Lexington, Kentucky, United States (Recruiting)
• Mayo Clinic Rochester — Rochester, Minnesota, United States (Recruiting)
• Saint Louis University Hospital — St Louis, Missouri, United States (Recruiting)
• Washington University of St. Louis — St Louis, Missouri, United States (Recruiting)
• Nebraska Cancer Specialists — Omaha, Nebraska, United States (Recruiting)
• Fox Chase Cancer Center — Philadelphia, Pennsylvania, United States (Recruiting)
• UPMC Hillman Cancer Center — Pittsburgh, Pennsylvania, United States (Recruiting)
• University of Wisconsin Carbone Cancer Center — Madison, Wisconsin, United States (Recruiting)

Study contacts

• Study coordinator: ClinicalTrials at Perspectivetherapeutics

Conditions Recurrent Melanoma; Metastatic Melanoma; Melanoma Stage IV; Melanoma Stage III; Melanoma; Theranostic; Radiopharmaceutical; Radiotherapy